Bifunctional Ligands in Discerning and Developing the Fundamental

and Medicinal Chemistry of B i s m u t h o

Glen G. Briand

Submitted in partial filfiliment of the requirrments

for the degree of Doctor of Philosophy

Dalhousie University

Halifax, Nova Scotia

Juiy 1999

@ Copyright by Glen G. Briand, 1999

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For Janice

Table of Contents

Table of Contents ...................................................................................... v

List of Figures ........................................................................................... ix

List of Tables .......................................................................................... x

Abstract ................................................................................................... xii

... ............................................................. List of Abbreviations aad Symbols xiii

Acknowledgrnents ......................................................................... xvii

. ......................................................................... Chapter 1 Introduction 1

1 . 1 Bifunctional Ligands as a Means to Denning the Coordination

Chemistry of Bismuth ............................................................... 1

1.2 Structurai Divmity in Bismuth Chemistry ....................................... 5

1 . 3 Characterization Techniques ......................................................... 6

.......................................... 1.4 Scope of Thesis and General Comments 8

1.5 Conclusions . Industry and the Scientific Method ............................... 9

Chapter 2 . The Chemistry of Medicina1 Bismuth Compounds: Hydroxy-/

Alkoxycarbox ylates and Inorganic Salts .................................................... 12

Introduction .......................................................................... 12

Inorganic Compounds ........................................................... 13

Carboxylates and Dexivatives ....................................................... 20

2 . 3 . Poiyhydroxycarboayfic Acid Complexes ............................... 20

................... 2.3.2 PoIyuminocarboxyJates and ~ioIatoc(~rboxyJutes 26

2.4 'ColloidaI Bismuth Subcitrate' (CBS). 'Bismuth Subsalicylate' (BSS)

and 'Ranitidine Bismuth Citrate' (RBC) ................................................ 27

2.5 Models and Alternatives for Bioactive Bismuth Compounds ................ 32

2.6 Interactions with Biomolecules and Phmaceutical Agents .................. 35

2.7

Chapter 3 .

3.3

3.4

Chapter 4 .

................................................................ 2.6.2 Amino Aci'ds 35

...................................................... 2.6.2 Pqptides und Proteins 36

2.6.3 Xnzeruc~ion of Bismuth Compun& witA Other Dmgs and

............................................................... Food Camponents 38

................................................................... 2.6.4 Antidotes 39

Conclusions ........................................................................... 40

Toward the General Synthesis of Dicarboxylates and the Structural

Characterization of Bismuth Oxdate .................................. .., .................. 42

Introduction .............................................................................. 42

Synthesis and Structure of Bismuth Carboxylates ................................... 43

............................................................... 3.2. I Carhxylates 45

.............................................................. 3.2.2 DicnrbaxyIates 49

................................................................ Results and Discussion 51

................................................. Conclusions and Future Directions 54

Aminocarboxylates: New Investigations into the Bi- System

.................................. Including Isolation of the First CatioNc Complex 58

Introduction ............................................................................. 58

......................... S ynthesis and Structure of Bismuth-Aniin&xy lates 58

............................................................... Results and Discussion 69

.......................................................... 4.3.1 Synthetic Shrdies 69

4.3.2 Prefiminary Electrosproy Mass Spectrometry Snidies of the

...................................................................................... Bi-&fa System 74

................................................. 4.4 Conclusions and Future Directions 75

......................................... Chapter 5 . Introduction to Bismuth Thiolate Chcmistry 78

........................................................................... 5.1 Introduction 78

......................................................................... 5.2 Monothiolates 78

............................................................... 5.3 Bifiinctional Thiolates 84

.................................................................. 5.3.1 Dithiolates 84

5.3.2 TIriuiatocarboxylates ...................................................... 89

..................................... 5.3.3 Hydroxy-/Alkoxy- and Ketothiolates 91

....................................... 5.3.4 Amino-, Imino- and Ara-Thiolates 95

....................................................... 5.4 Thio- and Dithiocarboxylates 101

.......................................................... 5.4.1 ThiocarboxyIates 102

5.4.2 Dithiocarboqdates (Dithiocarbamates. Dithioxanthates) ......... 103

.......................................................... 5.5 Summary and Conclusions 113

Chapter 6 . Definhg and Controlling the Arninoethanethiolate Chemistry of

Bismuth(III): Synthesis and Comprehemive Characterization of

..................................................... Homologous Thiolatobismutth Series 116

.......................................................................... 6.1 Introduction 116

............................................................. 6.2 Results and Discussion 118

.............................................. 6.3 Conclusions and Future Directions 130

Chapter 7 . (Methy1estei)methanethiolates: The First Ester Complexes of

Bismuîh(m) as a Step Toward Modeling 'Colloidal Bismuth

Subcitrate' ............................................................................................. 135

7.1 Introduction .................................................................... 135

7.2 Synthesis and Structure of Bismuth-Organocarbonyl Complexes .......... 135

7.3 Secondary Bonding and the tram ERect: the Role of a* Orbitals .......... 139

7.4 Results and Discussion ........................................................ 140

7.5 Conclusions and Future Direction ................................................. 147

Chapter 8 . Experimental ...................................................................... 151

8.1 General Procedures ................................................................... 151

8.2 Synthetic Procedures ............................................................... 151

8.3 Physical and Spectroscopie Data .................................................................... -160

8.4 X-ray Cxystallogcaphic Data ...................................................................... 168

References .......................................................................................... -173

viii

List of Figures

Figure 1.1 Bismuth bonding arrangements witb organic functional groups and their

heavier group 1 5 and 16 analogues ........................................................ 2

Figure 1.2 Bifunctional combinations for developing the chemistry of bismuth .......... 4

Figure 1.3 APCI-mass spectnun of bis(hydroxethane~olato)bi~~nuth(III) nitrate

550 in acetonitrile ............. .........-.... .......................-.....-................................. 7

Figure 3.1 Crystallographic view o f Di(C@,), 1, 0 8H20 38 .................................. 52

Figure 4.1 Crystallographic view of {[Bi(&&)], H} CI.2H20 ....................... 70

Figure 5.1 Bonding situations observeci for bismuth thiolate complexes .................... 114

Figure 6.1 Crystallographic view of Bi(SCH2CH2N&)3 hq .............................. 124

Figure 6.2 Crystallographic view of Bi(SCH2CH2NHJ2Cl =CI ......................... 125

Figure 6.3 Crystailographic view o f Bi(SCH2CH2NMe3, Cl 68(Me)C1 ................. 126

Figure 6.4 Crystallographic view o f the tetramer of Bi(SCH2CH2NMeC12

6C(Me)WiHCl 127 - ........................................

Figure 6.5 Crystailographic view of Bi(SCH2CH2NHMGC13 m(Me)CI .............. 128

Figure 6.6 Crystallographic view of Sb(SCH2CH2N&)C1 a C I .......................... 131

Figure 7.1 Crystailographic view of polymenc arrangement of

Pi(SCH,COOCH, )2Cl] ............................................................. 142

Figure 7.2 Crystallographic view of the dimeric arrangement of

[si(SCH2C0OCHJ3 ] ................................................................. 143

Figure 7.3 Crystdlographic view of the polymcric arrangement of

K p i {SCH(CH,)COO} C1J Iç .......................................................... 1 46

List of Tables

Table 2.1 Compound designatioas and assigned formulae for medicinal inorganic

........................................................................ bismuth compouads 14

Table 2.2 Characterization data for isolated bismuth hydroxy-/alkoxycarboxylates ... - 2 1

Table 2.3 X-ray crystallographic data for solids descnbed as colloidal bismuth

subcitrate .............................................................................................................. 30

................................. Table 2.4 Exarnples of other bioactive bismuth compounds 34

Table 3.1 Analytical data for carboxylate and dicarboxylate compounds ................... 44

................................. Table 4.1 Anaiytical &ta for aminocarboxylate compounds 59

............................... Table 4.2 Selected bond lengths for [ (Bi-Hm] complexes 73

...................................... Table 5.1 Analytical data for monothiolate compounds 79

........................................... Table 5.2 Analytical data for dithiolate compounds 84

Table 5.3 Analytical &ta for thiolatocarboxylate compounds ............................... 89

Table 5.4 Analytical data for hydroxy-/dkoxy- and ketothiolates ........................... 92

Table 5.5 Analytical data for amino-. irnino- and azathiolate compounds ................... 96

.................................. Table 5.6 Analytical data for tbiocarboxylate compounds 102

............................... Table 5.7 Anaiytical &ta for dithiocarboxylate compounb 104

......................... Table 6.1 Selected bond distances (A) for aminoethanethiolates 123

......................................... Table 7.1 Andytical data for carbonyl compouuds 1 36

Table 7.2 Comparimn of selected bond lengths (A) in bismuth-esterthiolate

................................................................... and related complexes 144

........ Table 8.1 Reaction conditions and isolation conditions for thiolate complexes 154

Table 8.2 Yields and elcmcntai analyses for al1 compoimds .................................... 158

Table 8.3 Complete vibrational chta for ail compounds ..................................... 160

Table 8.4 Melting points. prominent APCI-MS peaks. and 'H and "C NMR

Data for d l compounds ....................................................................... 164

Table 8.5 Peak assignments of the APCI mass spectra of

bis(hydroxyethanethio1ato)-bismuth salts [Bi(SCH,CH2 0 H ) A ................... 166

Table 8.6 MS/MS assignments for bi~ydr0xyethanCthiolato)bismuth~

saits Pi(SCH,C& OHXX] ................................................................ 167

Table 8.7 Crystailographic data for al1 complexes ........................................... 168

The serendipitous discovery and pharmaceuticd use of bismuth compounds,

dong with fùndamental interests, ha9 prompteci a cenhiry of chernical and clinical studies

of bismuth complexes and prepatations. The characteristic hydrolytic instability and

polymenc nature of these materials has detmed comprehensive chemical studies. As a

result, the chemistry of bismuth, as for many elements of the paioCic table, m a i n s in its

infancy. This work establishes the utility of bifùnctional ligands as a method to

overcoming these obstacles, and represents significant developments in the thiolate and

carboxylate chemistry of bismuth, the latter of which encompasses phamiaceutical

implications. The synthetic guidelines outlined are Wrely to be generally applicable to

other metals and various bifùnctionai ligand combinations.

List of Abbreviations

1 8-crown-6

APCI

avg .

bio.

bivv

br

BSC

BSN

BSS

calc

CBS

Ch

CI

ccord

conc.

con

cry s

cv

1,4,6,10,13,16-

hexaoxacyclooctadecane

atrnospheric pressure

chemicai ionization

average

biological

bip yridine

broad

bismuth subcarbonate

bismuth subnitrate

bismuth subsalicylate

calculated

colloidal bismuth

subcitrate

chalcogen

chemical ionization

coordination

concentrated

conduc tivi ty

crystals

cyclic voltammetry

c ysteine

decomposition point

dip yridine

Na-dimethy l fomamide

Na'-dimethylpropy lene-

urea

dimethylsulfoxide

dipivaloylmethanate

différentia1 thermai

analy sis

dithiocarbamate

dithioxanthate

p o l ~ g r a p h ~

elemental analysis

electnon impact ionization

electrospray ionization

Fourier transforrn

glutathione

glutaric acid

glycine

2-mercaptopropionic acid

Ha3mpa

H U

Hacac

H,bal

Hbdrnap

Hd-

H,cit

H,cvs

H,cvdta

H4cvdtpa

H,dapts

Hm

H&a

wz

Heacd

3-mercaptopropionic acid

aminobenzenethiol

acetylacetone

British anti-Lewisite

1,3-bis(dimethylamh0)-2-

propanol

4,s-benu>br,polone

citric acid

cysteine

zrans-c yclohexane- 12-

diaminetetraacetic acid

N- (2-aminoethyl)-tr~m-

1 2-diarninocyclohexane-

N-NW * *-pentaacetic acid

26-diacetylp yridine

bis(thiosemicarbazone

dirnethoxybenzenethiol

diethylenetriarninepenta-

acetic acid

3-mercapto- 1,s-

diphenylformazan.

dithizone

2-a~ninocyclopcnt- l -cm-

1-dithiocarboxylic acid

eth ylenediamintetraacetic

acid

ethyhaitolate

gallic acid

lactic acid

nitrilotriacetic acid

malic acid

2-methyl-8-

mercaptoquinolinol

maleonitriledithiol,

dicyanoethylene-

1,2-dithiolate

methionine

hexarnethylphosphor-

amide

N-hydroxyethyl-

ethylenediaminetetra-

acetic acid

Hm-hydroxyethyl-

nitnlodiacetic acid

Htnrr oxaiic acid

hTF

H,tar

H m

H,tsal

'Pr

IR

m

M'

Me

med.

mP

MS

pyridinee2,6-dicatboxylic

acid

D-(-)-penicillamine

phthalic acid

2-phenyl-8-

mercaptoquinolinol

quinaldic acid

salicylic acid

thiosernicarbazone

triethylenetriaminehexa-

acetic acid

human serurn transferrin

tartaric acdi

thioglycolic acid

thiosalicylic acid

isopmpyl

infrared

medium

molecular ion

methyl

medicinal

melting point

mass spectrometry

MT

MTP

M W

m/z

NMR

P m *

Ph

dEn

Pot

PP*

PreP

OY

Ram

pwdr

RBC

re f

tel.

RMBP

tandem mass

metallothioneh

metallothionein-Iike

proteins

molecular weigfit

mas-to-charge ratio

nuclear magnetic

resonance

paramet ers

phenyl

1,l O-phenanthroline

potentiometry

parts per million

preparation

Raman spectroscopy

ranitidine bismuth citrate

re ference

relative

S

sh

sol

sp

t

'Bu

TGA

thf -

singlet (strong w.r.t. IR

and Raman)

shoulder

solubiiity

sublimation point

triplet

tertiary butyl

thennogravimetric

analysis

tetrahydro fùran

tetramcethylsilane

tbiosemicarbazide

thiourea

ultraviolet-visible

spectroscopy

volts

very strong

weak

X-ray di fit tion studies

xvi

Firstly, I would like to thank my fiance Janice for her patience, understanding

and support, as well as our families for encouragement during both of our academic

careers.

A huge thank you goes out to Neil Burford for his optimism and motivation,

"profuse" promotion, camaraderie, and most importantly, for teaching me what it means

to be a scientist. "Press on, Neil!"

Gratitude is also extended to our collaborator Dr. T. Stan Cameron for sharing his

crystallographic expertise and being very accommodatïng over the past four years.

A special thanks to the past and present members of the Burford group for al1 their

assistance and discussions: Dr. Lisa Agocs for showing me the ropes; G. Bradley Yhard

for mass spectrometry instruction; Hamilton Maguire; Dr. Charles L.B. Macdonald and

Andrew Phillips for experimental aid; Dr. Daren Leblanc for crystallographic assistance;

Donna Silvert and Luke Y.C. Chen for experimental contributions; T. Danny Lawen and

Arthur House for reference management; and Denise Walsh for conversation.

1 would like to acknowleâge Drs. L. Rnmaley and J.S. Grossert, Brent Jewett,

Beata Kolakowski and Larry Campbell for mass spectrometry support and the Dalhousie

Mass Spectrornetry Centre for use of facilities; Drs. D. Hwper and M. Lumsden and the

ARMRC; Dr. K. Grundy for sitting on my cornmittee; Dr. RJ. Boyd for his suppon; and

Drs. W. Kwiatkowski and H. Jenkins for crystallographic assistance.

Thanks to our collaborators in microbiology and gastroentemlogy, Drs. D.

Mahony, P. Hof3tmaun, and S.J.O.V. van Zanten, L. Bryden and S. Lim-Momson, for

helpful discussions.

Many thanks to al1 of the fnends 1 have made during m y t h e at Da1 for making

my stay very enjoyable.

Finally, 1 would like to thank Dalhousie University, the Walter C. Sumner

foundation, MDS Sciex and Daihousie University for huidiag my meaifh

Chapter 1. Introduction

1.1 Bifunctiond Ligands as a Means to Definhg the Coordination Chemistry of

Bismuth

In light of the potential bioactivity of bismuth cornpounds, the prelude to this

project '" involvecl the synthesis of series of bismuth thiolate cornpoumis as simple

rnodels for complex commercial phamaccutical bismutth materials. A variation in

antimicrobial bioactivity among series members suggests a stnicture/activity relationship

for the bismuth environment,' highlighting the need for univenally applicable synthetic

procedures to control the coordination chemistry of bismuth. Further, the comprehensive

structural and spectroscopic characterization of systematic series of compounds

represents the most reliable fundamental foundation for rational chernical development.

This work represents significant advances in the thiolate chemistry of bismuth, a

movement toward development of generai procedures for preparing and studying the

chemisûy of bismuth carboxylates, and illusation of the role of secondary fitnctional

groups in bridging the gap between these areas. These goals have been achieved through

the preparative, spectroscopic and structural study of compounûs containbg bismuth

complexed with hydrocarbon ligands bearing two (bifùnctional) or more (polyfunctional)

donor sites, as shown in Figure 1.1.

Bifunctional ligands are excellent tools for probing the fiindamental and

biological chemistry of bismuth for various rca~011~. Firstly, they provide simplet models

of organic polyfunctional ligands, which are components of mcdicinal compounds such

\ Ch-Bi

O alkoxide S thiolate Se selemolate

-A Ch-Bi

ketone thione

0,0 carboxylate 0,s thiocarboxylate S,S dithiocarboxylate

organic amide

N amide

ester

amine phosphine arsint

Figure 1.1 Bismuth bonding anangemmts with organic fûnctional groups and their heavia group I 5 and 16 anaIogues.

3 as 'colloidal bismuth subcitrate' (citrate) and 'bismuth subsalicylate' (salicylate).

Secondly, introduction of the thiolate moiety stabilizcs components with respect to

hydrolysis and the precipitation of basic bismuth salts in aqueous media under various pH

conditions. Subsequently, this allows for the study of the interaction of the bismuth

center with other biological and organic hctional groups, and gives a greata

undentandhg of the role of bismuth in biological systems. Discussions in this thesis,

therefore, focus primarily on the chemistry of bismuth cornpouods containing the ligand

or ligand bgrnents show in Figure 1.2. These ligands facilitate the formation of five-

membered rings which have proven to be the most favourabk structural arrangement for

chelate complexes of Systematic alteration of one functionality imposes subtle

changes on the chemistry of bismuth. Ten of these bifiinctional combinations have been

studied to some degne in the literature or as part of this project and are discussed in this

thesis (designated by *).

B y emplo ying these bi fûnctional ligands, this thesis out lines some general and

important observations concerning the significance of chelate ability and pH in the

isolation of bismuth dicarboxylates (Chapter 3) and aminocarboxylates (Chapters 4) in

aqueous media. Similarly, control of the Lewis acidity and thiolation of bismuth are

explored (Chapter 6). and simple models for CBS and other bismuth complexes in

biologicai systems are developed (Chapter 7). Also provided as an introduction to these

topics is the preparation, structure and aqueous chcmishy of commercial bismuth

products and bismuth chemistry relevant to biologicai and medicinal activity (Chapter 2),

as well as the pnparation and structure of established bismuth thiolate compounds

Figure 1.2 Bihuictional combinations for developing the chemistry of bismuth. Designated compounds (*) have bccn used as rcagmts with bismuth, as discussed in this thesis.

5 (Chapter 5). Structurai studies demonstrate a variety of bonding situations which are the

basis for the rnajority of discussions in this thesis.

1.2 Structural Diversity in Bismutb Chemistry

As a main group heavy metal, compounds of bismuth exhibit immense structural

diversity with characteristics of al1 areas of the periodic table. The atom adopts covalent-

type bonding cornmon to main group elcments, and can accommodate Lewis bases to

fom labile adduct complexes typical of transition metals, which may include

intramolecular interactions (e.g. amino-lesterthiolates). Bismuth is the heaviest non-

radioactive element, and its large atomic radius (1 S2A) allows for higher coordination

numbea (typically three to tm) and more variable goometries than those achieved by

transition metals. As a consequence, bismuth is capable of coordinathg larger

polydentate ligands (e.g. polyaminocarboxylatcs. larger cmwn ethers) and extensive

intermolecular bonding. Secondary interactions are mediateci through introduction of

sterically bulky Ligands (e.g. 2,4,6-tert-butylphenylthiolate), manipulation of the Lewis

acidity of the bismuth center (e.g. electron withdrawing pentafluorothiophenolates), and

utilization of bihinctional ligands (e.g. arninothiolates), suggesting potential utility in

supramolecular chemistry and development of novel materials. Further, structural

diversity results h m relativistic effects which inducc an unpredictably variable

stereochemical activity or inactivity of the B i 0 lone pair.

In addition to their fiindamentai intacsf smictural studits play a key role in

establishing and confïrming accurate formulae assignments. As part of the extensive

6 c haracterization of compounds prepared in this thesis, several other techniques have also

been utilized.

1.3 Characterization Techniques

A majority of the compounds in this thesis have been comprehensively

characterized in both the solid state (EA, mp, FT-innurd and FT-Raman spectroscopies,

X-ray crystallography) and in solution ('H and ''C NMR spearoscopy, and AeCI or ES1

mass spectrometry). In addition to X-ray crystallography, m a s spectmmetry and

particularly FT-Raman spectroscopy have proven to be usefil techniques for product

identification.

Bismuth compounds are typically therrndy unstable, that is they decompose

before melting, and are of low volatility. Thmfore, m a s spectrometry sampling

techniques which involve heating the sample into the gas phase under high vacuum, such

as electron impact ionization (ET) and chernical ionization (CI), an generally not ideal.

Atmosphenc pressure chernical ionization (APCI) (see Figure 1.3) and electrospray

ionization (ESI) provide the advantage of introducing the sample in solution and involve

minimal (APCI) or no (ESI) thermal heating. Moreover, due to the high sensitivity of the

mass spectrometer, minimai sarnple concentrations are required.

Bismuth compounds, particularly bismuth thiolates, are strong Raman scatterers

below -3SOcm", a spectral region that is not typically pmbed by inûared spectroscopy.

This provides an intense and distinctive hgerprint for idcntifyîng recovered reactants

and new products. In addition, the speed and minimal ample preparation quired in

Figure 1.3 APCI-mas spcetnmi of bis(hyboxycthaocthiolato)bismuth(IIT) nitrate 550 in

acetonitrile.

8 collecting spectra establishes FT-Raman as a valuable technique for studying these

cornpounds.

Complexes prepared and discussed h m i n have been chosm based on specific

cnteria To enhance readability of this manuscript, some brief comments regarding this

topic as well as some generai remarks concemùig forrnatting of this manuscript are

provided.

1.4 Scope of Tbesis and Geaeral Comments

Since, the majonty of medicinai chemistry of bismuth involves Bi(m), this work

concentrates on the trivalent chemistry. Although there have been examples of Bi(V)

complexes of tropolone derivatives prepared a s potential antimicrobial agents,'v6 these are

not discussed in this manuscript.

In keeping with a biomimetic theme, al1 manipulations have been pedormed

without exclusion of water. Because of their hydrolysis to bismuth oxides in aqueous

media and theu minimal role in medicina1 chemistry, organo-bismuth compounds

(compounds containhg bismuth-carbon bonds) are generally not discussed, except to

provide a comprehensive account of a specific subsection. Also excluded fiom

discussion are complexes which involve bismuth as a Lewis base (e.g. bismuth-transition

meta1 complexes).

Generally. drawings are intendcd to illustrate connectivity and the coordination

geometry of bismuth only [dashed lines (-) reprcsent long or intennolecular contacts].

Drawings of these compounds aimed ai describing bonding features, such as Lewis

structures, are not meaningful or are misleadhg for bismuth complexes, while they are

9 employed for the description of some ligands. Crystallographic figures are drawn with

50% probability themal ellipsoids.

Tables of characterization data are pmenteâ in discussions of established

compounds to demonstrate the favorabili ty of product formation (i.e. yield) and the

reliability of structural and formulae wignments. The following series of reaction

equations, which are refmed to within cach table, incorporate synthetic reactants

describeci by the original authors and are intended to illustrate the breadth of synthetic

approaches employed. Reaction balancing schemes and by-products are not meaningfiil.

Previously prepared compounds and substrucnires are numbered according to the

chapter in which they are discussed, followed by a two or three digit nurnber signifjmg

the order in which they appear in the chapter (e.g. 309 signifies Chapter 3, compound

nine). New compounds prepared as a focus of this thesis are numbered by chapter

followed by a sequential capital letter (e.g. signifies Chapter 7, second compound).

General structures and bonding situations are n u m b d sequentiaily throughout the

thesis and are labeled with upper case roman numerals (e-g. II).

1.5 Conclusions - Industry and the Scientific Method

Industrial influence on the sciences is evident in this work through the study of

rnodels of commercial phamaceuticals and deserves a brief comment. On the one hand,

the need for "practical" science generates new ideas and directions that would probably

not be considered otherwise. However, th- is o f h a societal rrpuirement for

immediate applications, and problems potentially vise when prematwe conclusions are

10 drawn. A compromise involves assessment of fiindamental attributes with practical

appiication in the foreseeable, but not necessarily immediate, fùture.

Bismuth containing prepatations and compounds have been used for over 200

years to treat a variety of medical disorders. As a prirnary industrial interest for bismuth

chemistry, the pharmaceutical utilization of bismuth compounds would lead one to

believe that the mechanism of action of these compounds is well understood and their

pharmaceutical usage validated. In fact, the serendipitous discovery and use of these

compounds has led to centuries of medical empirical support with minimal underiying

chernical basis for these observations, yet they are still widely used today.

This is not to insinuate that studies in this area have not been numerous. Despite

difficulties associated in working with bismuth compounds several observations have

been made, but with few comprehensive chernical studies or general conclusions.

Further, vague and false statements plague the literature and have bem utilized as a basis

for conclusions and hypotheses for fiuther studies. This "snowball effect" results in the

misconception of acquired knowledge, and, therefore, the importance of valid

conclusions based on accurate empirical observations without over-interpretation must be

stressed.

The logical approach to understanding more complex situations, such as

biological systems, is rational and involves simpler, more e a d y understood models. The

fundamental knowledge gained in the process does not only provide insight into the

irnmediate problem, but also any othcr complex systern that we hope to understand now

or in the future. This thesis embraces this appmach.

I l In the author's opinion, the attractivencu of the following work is in the

simplicity of the approach employed. Therefore, there is the potential for an increased

appeal to a wider scientific audience and a decline in the number of assumptions required.

Despite its simplicity, some very g e n d conclusions can be made regarding not only the

specific topics addressed in this thesis, but about the systematic approach employed.

12 Chapter 2. The Chemistry of Medieinal Bismuth Compounds: BydroxyJ

Alkoxycarbosylates and Inorganic Sdts

2.1 Introduction

The bio-utility of bismuth and its compounds has a 250 year history, which is

described in a number of key review articles,'-" but the appearance of bismuth

compounds in the British Phannaceutical code^,'^" the French Phar~nacopeia,'~ the

Gexman Pharmacopeiam and the new Czechoslovalcian ~harmacopeia," is more recent.

Some compounds have been appmved for human use under the F e d d Food, Dmg and

Cosmetic Acp for more than 30 y-. After extensive use in the treatments of syphilis,

as well as other bacterial infections, the heavy metal label effected a decline in usage with

the advent of antibiotics, and incidents of revmible bismuth encephalopathy in France

and Australia in the 1 960's and early 1970's. Nevertheless, bismuth compounds remain

important components of stomach remedies, such as ~epto-~ismol. (bismuth

subsalicylate, BSS) and ~ e - ~ o l @ (colloidal bismuth subcitrate, CBS), and derivatives of

CBS, such as ranitidine bismuth citrate (RBC), are cumntly under development.

This chapter provides an overview of the data available for prominent bismuth

compounds which have been discoverex& developed or designed to have biological (with

the exception of botanical) activity or medicina1 utility, while a more complete review of

the topic has been written.l> A number of compoimds have been sufficiently well

charactenzed to assign fomulae accurately, however, a wide variety of materials,

mixtures or preparations containing bismuth have been examined and docurnmted, many

of which have ill-defineci fonnulae or vague name designations. The chernical aspects of

13 cornpounds for which definitive fomulae or characterization data are available are

discussed and compared. Tables 2.1 and 2.2 are lists of compounds with Literature

references to each item of characterization data.

2.2 Inorganic Compounds

The earliest bismuth compounds to be used for medical purpose were inorganic

bismuth salts, typically the basic bismuth salts, such as bismuth subniüate (BSN), which

was known as early as the 17'" centuy as "magisterium bismuti"." and bismuth

subcarbonate (BSC). A listing including assigned formulae and references to

characterization data are given in Table 2.1. Some named compounds have a variety of

formulae (e.g. subcarbonate and subnitrate) arising h m the variable preparations,

procedures and subsequential characterisation. Their designation as 'sub' salts has likely

been justified on the basis of high oxygen content and the a s s imen t of Bi-O moieties.

Most formula designations are baseci on elemental analyses and maybe overïnterpreted,

for example, bismuth hydroxides are sometimes written as BiO(OH), but could be

bismuth oxide (Bi203) with variable water content.

Bismuth is mined as bismuth oxide (Bi,03, "bismite") as well as the sulfide

(Bi$,, "bismuthinite"), the former of which may be prepared nom other inorganic

bismuth salts (nitrate subnitrate, subchloride, sulfate) by reaction with a carbonate or

alkali hydro~ide=~~ or by thermal decornpositi~n,~*~' or by other methods including

heating bismuth metal with sodium nitrate and hydrolysis of bismuth a lko~ides .~

Bismuth oxide existr as a number of polymorphs. a-, &, y- and 6-bismuth sesquioxide

form at various temperatures and have been studied extensively by DTA9' and X-raf7

Table 2.1 Compound designations and assigned formulae for medicina1 inorganic

bismuth compounds.

compound designation fonnula re ferences

oxide (bismite) Bi203 37

h ydroxide 3842

carbonate 40.46.47

basic carbonate 48.49

subcarbonate 50

- basic bismuth nitrate 71-74

subnitrate 75

Table 2.1 Compound designations and assigned fomulae for medicinal inorganic

b i srnuth compounds (continued).

compound designation fornula references

chloride/ trichioride BiC1,201 82

oxychloridd subchionde BiOCl203 83

subiodide U

oxyiodide Bi01 8s

aluminate 86.87

Bi2(Al20J3m 1 0H20 88.89

and neutron powder di~~tion.~' The crystaI structure of the a-oxide3' shows parallel

layers of oxygen atoms with bismuth atoms located between them. The oxygen atoms

form a pattern of three and five sided polygons, with the corners king bridged by

bismuth atoms in a three dimensional lattice. There are two unique bismuth atoms, one

five- and one six-coordinate, in distorted octahedral envhnments, the latter of which has

a corner of rernoved. Each bismuth atom has three short Bi-O bonds [2.08-î.î9A] and

two or three longer Bi-O contacts [2.48-2.80A].

The chlonde (BiCl, 201)~ and nitrate [Bi(NO,),.SH,O 2021" sdts of bismuth are

typicall y prepared fkom the reaction of bismuth oxide with the conesponding strong

mineral acids, and have both been stnicturally charactaited. BiC1,201" is molecular in

the solid state, witb one unique eight coordinate bismuth ceater. Each bismuth atom has

three closely bound chlorine atoms pi-CI 2.468-2.5 18A] in a near pyramidal

16 anangement and five long chlorine contacts Bi-CI 3.2 16-3.450AJ The nitrate

pentahydrate 202,' on the other hand, is ionic in the solid state, consisting of Bi3+ cations,

NO3' anions and lattice water molecules. Here, bismuth is bound to one asymmetrically

[Bi-O 2.60(1) and 2.99(2)A] and two symmetrically p i - O 2.43(2)-2.66(1)A] chelated

nitrate ions, and four water moiecule oxygen atoms [Bi-O 2.32(1)-2.67(1)A], giving a ten

coordinate geometry.

In weakly acidic to basic conditions the inorganic salts are "hydrolysed" to the

corresponding oxide products, commonly refcrred to as "basic," "oxy-" or "sub-" salts,

which have a tendmcy toward the formation of the favorable BiO' bismuthyl subunit.

Such is demonstrated by the hydrolysis of bismuth chlonde in water to form bismuth

oxychloride:

2.1) i3iC13(s) + H20 BiOCl + 2 HCl

It has been argued that the solubility of BiOCl in acid species is not simply due to the

liberation of Bi" b m BiO' by the hydronium ion," but to the formation of the anionic

species ~iCl,? Supporting data include the greater solubility of BiOCl in hydrochloric

17 acid than in nitric acid, and the increase in solubility of BiCI, and BiONO, in nitric acid

with the addition of NaCI. Solution studies of the cornplexation of bismuth(m) with the

chloride ion encompass not only aqueous mediaM but also organic sol vent^.^^-^

Investigations into aqueous reactions of bismuth ~hlonde'" '~~ involve the effect of

temperature on hydr~lysis '~~ with formation of BiOCl203, BiOCI*2H20, and BiCI, *H,O

solid phases,'(" while the hydrolysis of bismuth subiodide has similarly been s t ~ d i e d . ~ ~ ~

The crystal struchue of BiOCl 203,1M the only sûucturally characterized hydrolysis

product of BiCl,, shows one unique eight cwrdinate bismuth center smunded by four

oxygen atoms and four chlorine atoms [Bi-O 2.3165(12) A] and pi-CI 3.059(8) A]. The

atoms create asymmetric decahedrons around the bismuth centers, which are linked in a

three dimensional array.

203

Unlike the hydrolysis of bismuth chionde, the lability of the nitrate ion allows for

a muc h greater range of hydrolysis products of bismuth nitrate,"s7ss107-' " with product

fomation (degree of hydrolysis) being sensitive to specific precipitation condition^."^'^'

The majority of these products have been identified by physical techniques, such as

chernical analysis, while species in solution have been detemllned by electrical

cond~ctivity."~

This sensitivity to &on conditions is dwonstrated by the fomation of:

[Bi,0,(OH),)(N0,),*3H20 204.~" (modified formula BiONOpO. 1Bi,03@0.9H20),

18

ob tained in the 1.2 to 2.4 pH range; slightly l a s basic [Bi,04(OH)4 ](N03),*H20

(modified formula BiON03@0.SH20), isolated by crystaliizing Bi(NO,),*SH,O fiom

boiling O.OSM m O 3 or by heating crystals of ~i,O4(OH),I(NO,),a4H2o; and

[si60,(oH)4](No3),*4~ 204cZ4 (modified formula BiON03*H20), recovered as the

h t solid hydrolysis product below pH 1.2. The structures of al1 three compounds are

very similar and are composeà of [B~,O~(OH)J('@'"~ hexanuclear poiycation ciusters 204

204

with loosely coordinated bidentate nitrate anions and water molecules. The hexanuclear

units 204 show six bismuth atoms sitting at the corners of a slightly distorted octahedron

with the eight oxygen atoms capping the octahedron faces. The structure of

i60,(OH),] (N03),.3H,0 2 04 is composed of [Bi60,(OH),]" cages, which dimerize

through a Bi-O edge. The Bi-O bond distances fdl into three ranges, comsponding to

the Bi-O,,,, [î. 10(4)-2.23(3)A], Bi-Ob- [2.22(4)-2.52(3)A], and Bi-OWnI [~.ss(~)AJ

bonding situations. The stnicture of [Bi,04(OH),](N03)6.H,0 204bn-m contains a

monomenc hexacationic [Bi604(OH)4]* cluster with four oxide oxygen atoms and four

hydroxide oxygen atoms. A short Bi-O*, [2.62(3)A] and a short Bi-O,, [2.64(3)A]

contact gives two five-coordinate bismuth atoms. The structure of

[~~,O,(OH),I(NO,),@~H,O 204eU shows a simiiar arrangement.

19 Further evidence for the preferred formation of the bismuth-oxygm polycation is

its presence in the hydrolysis products of bismuth perchlorate in s~lution'"'~ and in the

so lid state in the hydrolysis product ~i604(OH)4](C104)p 7H20 204d.I"

Bismuth oxide itself may be hydrolyzed or hydrateci [e.g. Bi(OH), bismuth

hydroxide, BiO(OH)], and aqueous mixtures have been studied at various pH

v a i ~ e s . ~ ~ ' ~ ~ ' ~ ~

Bismuth carbonate may be formed h m the reaction of Bi203 with excess CO,, or

the reaction of Bi(NO,),-SH,O with excess Na&03 or K2C03."-"JU5 As with bismuth

subnitrate, the composition of bismuth subcarbonate is sensitive to reaction conditions.

This accounts for references to "light" and "heavy" bismuth subcarbonate and subnitrate

in the phamaceutical and medical literat~re,'~' which exhibit variable therapeutic action

depending on basicity and degree of subdi~ision.'~'

"Bismuth aluminate" is a variable composition of Bi203, N,03 and H,O and

possibly CO,. It is employed maidy as an antacid, combining the antacid properties of

the basic bismuth and aluminurn oxides.

Of the inorganic salts employed in medicine, only bismuth chloride, oxychloride,

and nitrate pentahydrate have definite compositions. The variability in the subnitrate,

subcarbonate, hydroxide and aluminate results h m the sensitivity of product formation

to reaction conditions. This variability in composition may account for variability in the

2.3 Carboxylates and Derivatives

2.3.1 Hydro~carboxylc Acid Complexes

Bismuth complexes of hydroxycarboxylic (aliphatic hydroxy acid) acids,

including galiic (Ha, tartaric (FI&), lactic 0, malic (Hgai), and citric ( H m

acids, have been used in a wide range of medicinaî capacities since the tum of the

century. An ovemiew of the characterization data that have been obtained for isolated

bismuth polyhydmxycarboxylates is pnsenied in Table 2.2.

As with bismuth subnitrate, the lability of the bismuth-carboxylate interaction

allows for variable compositions of these compounds, which are very sensitive to reaction

condition^.'^^*'^'^ Moreover, the fonnulae arc somethes speculatively wigned on the

basis of preliminary identification.lY There have becn two crystallographically

2 1 Table 2.2 Characterization &ta for isolated bismuth hydroxy-/alkoxycarboxylates.

Compound designation

Formula Characterization Data

basic bismuth EA'33 gallate

gallate E A ~ ~

Na Bi Gallate prep, EAt3'

Na Bi Digallate prep, EA'~'

Na Bi Me Gallate prep, EAl3'

oxyiodogallate C,H(OH),(CH,)COOBi(OH)I prep,136 mp137.138

"Airo1"

iodogallate DTA'~'

tartrate PreP, 139 ~ ~ , 1 * 1 " IR143

acid

bismuthotartrates lRt~s

sodium ûibismuth COO(Na)CHO(BiO)CHû@iO)COO- pnp" tartrate

sodium bismuth PreP, 147 ~ ~ , 1 4 8 ~ ~ ~ 1 3 0

tartrate

d- and meso- BiO(H&@nH,O, prep, IR'"

d-Bi(H&g)(Hm .3H20, dl-MBiO(H& and M B i w

B i ( H a ( H a . 3 H 2 0 prep, EA, XRHO

MBi(Hw (M = K, Na, Li, NH,, Hpy) prep, IR"'

KBiO(H&), K B i W p q , IR152

Bi2H2(&),, NaBi2O2HW prep, EAlS3

Table 2.2 Characterization data for isolated bismuth hydroxy-Ialkoxycarboxylates

(continued).

Compound Formula Characterization Data designation

NaBiO(Ha, Na(BiO),m P ~ V ' ~

Bi2(Hw3*2(H&) prep155

Bi Na acid tartratc prepI6

sodium potassium EA"~ bismuth tartrate

prep, XR1"

bismuthate(III) hydrate

malate Bi(pab*H20 prep, EA, XR'"

citrate prep, EA, 14' DTA' 'O

Bi(Hç-) P ~ V "

Bi(H&) aH20 prep, ïR, DTAI6'

Bi3(Hcith(OK)3 prep, EA'"

"pentabismoi" 16NH,OH. 1 lBi(H&).Bi(OH), P W ' ~ ' "

*6H,O

bismuthocitric acid ~ r r ~ ' "

sodium bismuth P~V" citrate

23 Table 2.2 Characterization data for isolated bismuth hydmxy-/aikoxycarboxylates

(continued).

Compound Formula Characterization Data designation

dibismuthyl sol'* monosodium citrate

characterized bismuth tartrate compounds, which arc isostnictural and involve two five-

membered bidentate chelate ligands. In the ammonium salt, NH4[Bi(H,tar)Z(H,0)] .H,O

205,"' four bidentate doubly deprotonated tartaric acid ligands surround each bismuth

center. The two crystallographically unique ligands an bound to the bismuth center via a

carboxylate (O1) and an a-alkoxide (e) oxygen atom Pi-Odx,, 2.372(7) and

2.438(6); Bi-Odw* 2.462(6) and 2.460(6)A] fomiing five-membered rings. One of these

ligands bridges a second bismuth center in a similar manner via its remaining carboxylate

(O6) and the a-hydrox y (O4)groups Pi-O,*, 2.608(6), Bi-O-YIK 2.622(6)A]. This

carboxylate group asyrnmetrically chelates a third bismuth center in an 0,O' (os, 06)

manner ~i-Oo,,~-,,,,x,,k, 2.476(6) and 2.738(6)A] forrning a four-membered -BiOCO-

ring. The oxygen atom of a water molecule completes the coordination sphere [Bi-O,,

24 2.400(6)& for a total coordination number of nine around bismuth and a ûigonal

prismatic geomehy. The resulting structure is a complex one-dimensional coordination

po lymer with extensive hydrogen bonding. The complex B i(H&&(H&Q.3H20 206Is0

contains a singly deprotonated (Hm- tartrate Ligand, but retains an analogous structure

to the ammonium salt [Bi-O-* 2.381(10)-2.615(11); Bi-Omy 2.467(9)-2.588(10);

Bi-Oo,,.-x, 2.482(10) and 2.754(11); Bi-O, 2.409(9)&

There have been several solution studies of bismuth tartrate compounds and

systems 148.173-1 75 emplo ying several spectroscopie and physical t ethniques including

vi~ua1, '~~ spectrograp hic1" and solubility methods,"' optical rotation @-tartrate), ' " ' H

NW 17' polarirnetxy, 174.177.179 p~tentiometry,'~'" p o l a r ~ g r a p h y , ~ ~ . ' ~ ' ~ ~ e lect r~rnetry '~~~~~'

and o~cillography.'~~ These approaches have been employed to detennine the

corn position^^^^^'^ and stability constant^'^^^^^"^ of complexes at a variety of pH

valUeS 180.1 8 1, '861 88 and at various tartrate con~entrations.'~~~" mer investigations involve

extraction of bismuth tartrate complexes nom solution using diisoamyl amineIag and

hydrolysis studies with the isolation of NaBiO(Hu and Na(BiO),(tar) sodium bismuth

"sub"tartrate cornplcxes. lw " Few bismuth compounds of lactic acid (Ha have been

reponed.lU.IS8.1J9.162.163.191.192 Bi(Hlac), 207,'~' the ody structurally characterized example,

shows three chelating lactate ligands, dl of which are singly deprotonated at the

carboxylate fûnctionality and fonn five-membered -BiOCCO-rings. Two of the ligands

are tightly bound [Bi-O,, 2.205(7) and 2.364(8); Bi-Oh*y 2.474(8) and 2.457(9)A],

while one is weakly bound [Bi-OWy, 2.628(9)& Bi-OhWy 2.800(1)A]. The

carboxylate group of the weakly bound ligand coordinates a second bismuth center

25 asymmeeicaily in an O,Ofmanner [Bi-O 2.328(9) and 3.104(9)& forming a four-

membered -Bioco- ring. The exocyclic carboxylate oxygen of a tightly bound ligand

coordinates a third bismuth center [Bi-O 2.580( 1 )A], giving each bismuth atom a total

coordination number of nine and an overall complex three-dimensional network structure.

A mixed lactate-tattrate complex dilactatobismuthotariaric acid C,J-i,,O,,Bi has also been

prepared nom the reaction of lactic acid with Bi nitrato tartrate,'" while no solution

studies of bismuth-lactate systems have been reporteci.

As with lactic acid, few bismuth complexes of malic acid have been

prepared. 162.191 The single stmcturaily characterizcd exarnple Bi(mai)aH,O 2 0 8 ' ~ shows

bismuth chelated by four triply deprotonated malate ligands in various modes pi-O3

2.244(6) and Bi-O' 2.407(8)A; Bi-O' 2.255(6) and Bi-0' 2.571(9)A; Bi-O' 2.959(9) and

Bi-o2 2.553(8)A; Bi-O' 2.351(9) and ~ i - O s 3.233(9)A] fomiing a five-membered, a six-

membered, and two four-membered rings. The oxygen atom of the lattice water rnolecule

pi-O,, 2.80(1)A] completes the coordination sphere for a total coordination number of

seven. The bonding of each ligand to four bismuth atoms again rrsults in a highly

coordinated polymeric network.

Few solution studies of bismuth-maiic acid systems have been performed and al1

involve physical methods, including ele~trometr~,'" polarirne~y,'~~ p~larography,"~

oscillography1" and a bismuth ion-selective electrode.'" Stability constants"' have been

detexmined at various pH and malic acid concentrations. lg3

2.3.2 Poïyaminocarboxylates and Tliioiatocarboxylnres

In addition to hydroxycarboxylic acid complexes, bismuth complexes of the

polyaminocarboxylic acids nitrilotriacetic acid (Hm, also commonly referred to as

triglycollamate, and ethylenediaminetetraacetic acid (Hm have also been employed in

medicine" and pharmacy and studieû phamia~ologically.'~~ Similariy, a number of

bismuth complexes of the thiolcarboxylic acid ligand H m have been assessed for

pharmacological'96 and antimicrobial activity. Synthetic and structural data for isolated

bismuth Bi-- and Bi-sdta complexes is presented in Chapter 4.2.

HOOC, /-\ +00H

HOOC N N OOH HOOCJ ~ O O H

27 There have been several studies of Bi-- complexes in sol~tion,'~' at various pH

and employing both ~pectroscopic '~"~~ and physical"3.'9"w0'50

techniques. A number of physical constants have been determined for these systems

including f~nnation,'~' stability,'"3*'9g2003033205 protonati~n,~~~ hydrolysi~;~~ and rate

constant^,'^' as well as dissociation potentials2& thamodynamic f û n c t i o n ~ ~ ~ ~ and

mechanism of complex formation? The interaction of and edta with BiCl2- has also

been studied. For the bismuth-& system, both s p e c t r o s c ~ p i c ~ ~ ~ ~ ~ ~ ~ and

physical 183. I8SMl20C2O7,2W,.2"PI techniques have been employed to detennine complex

composit ions~ dissociation potential~?~ molar ab~orbances,2"~ and

stability, I832ûbZ05207tl I.ZIV~Z-224 protonation constants,'OS as well as hydrolysis constants20s

and k i n e t i ~ s . " ' ~

Isolated bismuth complexes of thioglycolic acid include bismuth dithioglycolic

acid,=' ~i,(tga)~ca,,~~ ~ i ~ ( t i t g â ) , = ' Na Bi thi~glycolate,'~

ethylbisrn~thothiogiycolate,~% and Bi thioglycolate-triamide,'% while Bi-tgê solution

systems have been studied by spectroscopie techniques ~ n l y . ~ '

2.4 'ColIoidal Bismuth Subcitrate' (CBS), 'Bismuth Subsalicylate' (BSS) and

'Ranitidiae Bismuth Citrate' (RBC)

Citrate salts of bismuth represent the most extensively studied series of bismuth

compounds by virtue of the widespread medicina1 use. Bismuth citrate is essentially

insoluble in water, but a dramatic increase in solubility with increasïng pH has been

exploited as a bio-ready source of soluble bismuth, a material referreâ to as colloidal

bismuth subcitrate (CBS). Formulation of these solutions is complicatcd by the

28 variability of the bisrnuth:anion stoichiometry, the presence of potassium a d o r

ammonium cations, the susceptibility of bismuth to oxygenation to Bi=O and the

incorporation of water in isolated solids. Consequently, a variety of formulae are

classified in the literame as CBS. [ J ' v ' J 4 . ' 6 2 - ~ ~ . l 6 6 . 1 6 7 . I ~ U o ~ Solutions have been examined

by a variety of approaches, including visual studie~"~ and physical 1 8 3 - I B S . I W . I ~ ~ . Z ~ ~ , Z ~

techniques, to determine corn position^'^^^ and stability constant^'^' of bismuth citrate

solution complexes. at various p~"'*'" and citrate concentration^.'"'^^ ' H and I3C NMR

spectroscopy indicate rapid exchange of citrate moieties at low concentration and

the existence of oligomeric or polymeric units at higher concentrations.

Solids isolated fiom various, often ill-defined combinations of bismuth citrate,

ch i c acid, potassium hydroxide or ammonium hydroxide have been assigned formulae

on the basis of elemental anaiysis data or by determination of water and ammonia

Additional speculation is made for their presentation as modified fomulae

(& = C,H,07'-; H& = [C02CH2C(OH)(C0&H2COJ3-), however, assignments for such

complex systems are of low significance in the absence of complementary data other than

thermal analy~is,~' infiard spectroscopp7 or NMR spectroscopy."' In this context, the

Merck index lists the chernical fonnula of CBS as K,(NH,),i)i,O,(OH),(Ca,O,), in the

1 lth e d i t i ~ n , ~ ~ but in the most recent edition provides a less precise name 6'trip~tassium

dicztrato b i smu~hate"~~.

More defmitive formulae have been detemiined by X-ray crystdlography and are

listed for structural cornparison in Table 2.3. The conditions for isolation of these

crystalline materials fkom solutions similar to those denned above are provided in some

cases, but are sometimes incomplete and often involve time periods of months. Isolation

29 of the sodium salt 213 was somewhat unusual in that it was unexpectedly obtained fiom

reaction mixture of ranitidine bismuth citrate, glutathione, D20 and NaOD?'

The structures in Table 2.3 are al1 closely related and are generally composed of a

citrate anion (çif) intimately bound to a bismuth center, an appropriate number of

potassium or ammonium cations (to balance the charge) and solvated or coordinated

water molecules. Thme of the structures 214-16 contain an additional citrate trianion

(Hçir = C6H,0T) and one stnicture 216 is constnicted around a hexanuclear bismuth

oxygen cluster @&O,), similar to that found in bismuth subnitrate (204). The

stoichiometries of the components are variable, including the bismuth citrate relationship,

but most involve a well defined chelate interaction with the tridentate citrate bismuth

complex. The potassium and ammonium cations are essentially interchangeable, and the

ammonium salt 21 1 is isostructural with compound 212. The variety of reported

structures is somewhat misleadhg when one recognizes that of the eight structures listed

in Table 2.3 (nine structural types have been previously incomctly propo~ed'~), only

compounds 214-16 c m be considereà unique. Structures 209-13 are constructed from the

simple monoanionic complex. composed of Bi3* with a tridentate citrate tetra-anionic

ligand. This unit is also evident in 214-16, but these structures involve additional

Table 2.3 X-ray crystallographic data for soli& described as colloidal bismuth

subcitrate.

Formula Bi:& Coord Space Ce11 ratio # at Bi Gmup param., a, b, c, P

K(Bi&(H,O), 2OP4' 1:l 9 P2,h 10.924, 15.280, 14.967, 1 05.48

%.5(NH4)0.5(sim@20)3 3 1 p 1:l 9 P2'/n 10.923, 15.424, 15.037, 105.67

(MII)(B~&)(H~O)~ 21 1''' 1:l 8 C2/c 16.805, 12.544, 10.401,91.27

k.5(NH,)a5(siW(H20)2 212- 1:l 8 C2k 16.860, 12.395, 1O.328,9 1.79

N~(B~&,(H~o), 2 1 3 ~ 1:l 8 C2/c 15.723, 13.899, 10.423,94.39

L.,S(NH~)~S(~~UOZ(H~(HZO)I~ 214U3 2 3 9 P- 1 1 1.801, 12.973, 15.856,98.15, 108.39, lOO.9l

(NH,),@ici~)(Hcit)(H,O), 2 W 3 1:2 8 P2,k 8.998, 9.492, 27.021,99.42

(NH,)6(Si604)&4(HZO)I 2 16 235343 3:2 R-3 17.807, 17.807, [initially assigned 3 1.596 (NH4)6(si604oH)&(H,0)5Ha

chemically different units. This unit together with one or two cations and three or six

water molecules, defines the asymmetric unit of compounds 209-13, but adopts a well

defined dimeric arrangement imposed by chelate coordination of the pendant carboxylate

moiety to a neighbouring bismuth centcr. Différences in the macrostructures of

compounds 209 and 210 (P2,/n) and 21 1-13 (CUc) result h m distinctions in the

interactions between these dimers, which is likely only a fiinction of the degree of

hydration, i.e. the number of water molecules coordinated to bismuth. Compounds 214-

31 16 aiso involve the tridentate coordinatcd citrate tetraanion 0. However, the presence

of an additional citrate trianion (H& = [C02CH2C(OH)COtCH,COJ*), and an additional

citrate tetraanion for compound 214, cornpikates and opens the structures, enabling the

incorporation of additional water. Nevertheless, the familiar pendant carboxylate bound

dimer is evident in 214 and 215. Although compound 216 does not display the distinct

dimer unit, the tridentate chelation of one of the N o unique bismuth centers is clear.

The ubiquitous tridentate citrate chelation of bismuth, which has also been

observed for aluminum citrate complexes,"' implies a special stabili ty for the

b i scarboxylate/alkoxide interaction enforcing a pendant carboxylate. The coincident

coordination of this third carboxylate is precluded by the required tetrahedral geometry of

the central carbon center of the citrate anion. The consequential five- and six-membered

chelate heterocycles are favoured over two seven-mernbered heterocycles imposed by

coordination of three carboxylate oxygen atoms. More importantly, the alkoxide has a

substantially higher basicity than the carboxylate. In the carboxylate chemistry of

bismuth, the citrate salts are uniquely water soluble at high pH with avoidance of

hydrolysis, which typically gives Bi0 for other salts. The tridentate chelate involving the

alkoxide dominates this behaviour relative to other polycarboxylates and relative to

bismuth citrate [Bi@?&)] at neutral or low pH, which is deprotonated at high pH.

The very low solubility of bismuth subsalicylate (BSS) has hindered

charactensati~n,'~*'~~ while the more reccntly developed ranitidine bismuth citrate (RBC)

217, a new therapy for peptic ulcer diswe, is highly water-soluble. RBC is obtained

fiom the reaction of ranitidine hydrochloride [N,Naimethyl-5-(3-nitromethylene-7-thia-

2,4-diazaocty l) hican-2-methanamine] and bismuth citrate. Characterization has included

32 elemental analysis, 'H and "C NMR and IR spectmscopy, polarography and X-ray

powder di fn-action, however, definitive structural assignmmt has been complicated by

extensive hydrogen bonding. The proposed structure is speculated to involve the

formation of a five mernbered ring by chelation of the bismuth center by NMe, and

salicylic acid (Hîsal) rani tidine

2.5 Models and Alternatives for Bioactivc Bismuth Compounds

The apparent chernical complexity of the commercial bismuth containing

phannaceuticd agents, which is imposed by the lability of the ligands has prompted the

development of simpler mode1 compounds and the search for alternatives to the

established systems. Therapeutic or anti-bacteriai activity has been speculated upon or

suggested for many bismuth compounds, and some have been assessed in vivo and/or in

vitro. Table 2.4 lists examples of compounds for which a medicina1 effect has been

suggested or evaluated, together with the preparative method. Most compounds of this

type are superficially chancterizd and the molecular structures or even the fonnulae

have not been defked, with some cases illustrating varying composition depending on

speci fic reaction condition.24uw

33 Systematic and comprehensive synthetic studies have recently been coupled with

bioactivity snidies to confirm the bio-significance of bismuth and reveal important trends

in activity. Extensive series of bismuth (Xi) and bismuth (V) tropdones and bismuth

(III) thiosemicarbazones and dithiocarbazonic acid methylester derivatives have been

assessed for their anti-HelicobacterpyIori activity illustrating a substantialiy lower

minimum inhibitory concentration for the f~rmer .~

tropolone thiosemicarbazone

As a heavy metallic elemmt, bismuth has a prominent thiophilicity responsible

for the facile fornation of sulfido and thiolato complexes, and a consequential

thermodynamic and kinetic stability, which has enabled synthesis and isolation of the

most extensive array of denvatives. Numemus examples have been assessed for their

bioactivity, but more irnportantly systematic series of compounds have been prepared and

evaluated. Antimicrobial bioactivity assessrnent of three systematic senes of

comprehensively characterised thiobismuth compounds, 2 17,2 182 and 21 9) (syntheses

and characterization of these compounds are dimwed fiuther in Chapter 5.3), against

CZostridiurn dtJTcife, Helicobacfer py lori, Escherichia col& Pseudomonas aemginosa and

Proteus mirabilis reveals significaat differcnces in activity across each series, suggesting

a structure/activity relationship for the bismuth environment.' In addition, a rat mode1 of

gasûic ulceration has revealed distinct differences in the ulcs healing efficacy of the

Table 2.4 Examples of other bioactive bismuth compounds.

Compound formuia Chernical (BioJ Suggested or Ref designation Med.) Dam evaluatcd

medicinal efkct (Mode of AAmin.)

phenylbismuthbis PhBi(Cfi4N0S), p r q ~ (in vino - dctcrgents, soaps, (2-pyridinethiol grun positive, shampoos 2s 1

1 - oxidc) gram negative)

organobis(thio- C&@@C&C~-P)D prep, Jpecttoscopy bactericide 252

phenylato) CH3Bi(SC6H4NH2-~)~ bismu th(m)

m-1 r m ~ 3 i ( s c d r ~ ~ ~ r n ~ - ~ ~ r , [CH~B~(SC~H~NH~CH~-PW W 3 I 2

3-phenylthio- and Bi salts of Pfcp ulccn s 3

phcnylsulfonyl- RC,H,S(O),CH=CHCO,H (cytoprotec tive acrylic acid (R = H; halo, C,, alkyl or alkoxy, aad gascric acid bismuth salt NO,; n = 0.2) secretion-

inbiiitory)

p-chlorophenoxy- mono- and bis- PreP depressan t for 2s

isobutyric acid ~CI(C~,)OC(MC)~CO,H salts blood cholcstcrol bismuth salt

bismuth Bi(SC&i4CONH3, P m * sol (ointments, talc) 35

O-mercapto- (fiiagicidal, benzamide bactcricidal

activity)

dipropylacetic acid Bi[(C,H,),CHCOd, P m , mP, sol throat infections bismuth salt (rectal suppository

witb cocoa butter)

p-amino- and p- [Bi(C,HSIJO,),) 1, Prtp nibcrculostatic m berizamidosalicylic [Bi(C,,H,a04)J12 acid bismuth salts

bismuth O-AcOC&CO~iO pmp (stable in intestinal (oral. 2 s

subcompounds stomach - no data) rectal)

bismuth C4HJN40,aBi(OH)2 Pr- external and 3 9

allantoinate intemal ulccrs, wounds, etc.

basic bismuth C&(OH)(OCH,)CûûBiO prep, sol syphilis a50

guaiacol- (ointment, carboxylatc subcutancous)

bismuth hydrox y- Bi(OH),ûC&N PrcP, sol (antiseptic on 26 I

quinolinate wounds)

double iodide of w t i n e e 2 ~ ~ a 1 P m , (gehtin capsules) as emctine and bismuth

ethylene = (CHJJ derivatives of compounds 217 and 218.2a

I Bi \

S \

R R Bi-S

\

S, ,S R 's'

2.6 Interactions with Biomolecula and Pbumaceutical Agents

One proposed mode of action of mti-ulcn bismuth compounds is the ability of

bismuth to bind to proteins of exposed tissue and provide a protective coating over the

~lcer.~' It is crucial, therefore, to have an understanding of the bismuth bonding ability

of amino aciàs, proteins, and other biomolecules, which may also provide a basis for

conclusions of phamacological and pharmacoicinetic snidies. Further, bismuth

complexes of amino acid derivatives, such as D-peni~illamine~~ and other

dialkyl~~steines ,~~ have been suggested for medicina1 use, while polypeptide complexes,

such as those of glutathione, have been suggested for tteatment of syphilis and other

disea~es."~ Investigations of systems and isolated wmpounds incorporating bismuth and

amino acids or other biomolecules are described below.

2.6.1 Amino Acids

The bismuth methionine complex ~ i - 1 2 ~ was prepared in non-aqueous

media and chanicterized mainly by infked spectroscopy. The reaction of a slight excess

of cysteine ( H a , which contains a thiol fiinctionality, with bismuth subcarbonate in

3 6

aqueous media gave Bi(ÇrsH)pH20, in which the ligand retains one labile proton.*"

This compound was also characterized mainly by idhred spectroscopy. A bismuth

R = H, glycine

O I O H

= (CH&NH2, lysine = CH20H, serine = CH2SH, cysteine

R m 2 = CH2(CH3)tSH, penicillamine

= CH2CH2SCH3, methionine

cornplex of D-(-)-pdcillamine [ B i ~ C l ] , a cysteine dimethyl derivative, has

been structurally characterized and is discussed fhther in Chapter 5.3?

Solution studies of bismuth amino acid complexes include amperometry of

bismuth-glycine complexe^,^" spectrometry of cysteine complexes~" pH-metric

investigations of L-lysine complexe$" and polarognphy of serine complexes2".

2.6.2 Peptides and Proteins

The complexation between RBC and the tripeptide glutathione WH) (y-L-Glu-L-

Cys-Gly) has been studied in both aqueous media and in red blwd cells via 'H NMR

s p e c t r o s c ~ p ~ ~ " ~ ~ ~ and sulfur has been found to be the sbongest binding site for bismuth.

Stability constants have been detexmined for the Bi(&), species, and binding was found

to be cornpetitive between @H and ieQfê and is pH dependent.

glutathione (&H)

37 The binding of the Bi3' cation to hurnan senun transferrin @TF), an iron transport

glycoprotein, has been examined by W-vis and NMR spectroscopies,2n27' while the

effect of the concentration of bismuth on plasma protein and red blood ce11 binding, as

well as bismuth binding to human senun albumin, bovine serum albumin and hurnan

S e m , have also been studied?) The interaction of CBS with erythrocytes and

erythrocyte lysate has been investigated using 'H spin echo NMR2.0

The binding of tripotassium dicitrato bismuthate to the bile acids has been

investigated in vitro using 'H labeled acids and measuring radioactivity at high and low

PH."' Bismuth was found to bind each acid to varying degrees and only at low pH (2.0),

suggesting a mode of action in ulcer healing. Pepto-Bismol, as well as its individual

components bismuth subsalicylate and montmorillonite, have been found to sequester bile

acids fiom aqueous solutions in vitro."' Other studies examine the effect of pH on the

formation of bismuth protein complexes2u and bismuth-gelatin c o r n p o ~ n d s ~ ~ the

interaction of bismuth compounds with alkaline protein solutions under the biuretic

reaction condition^.'^^ and the behavior of elemental bismuth with various proteins under

anaerobic conditions. 286.287 Bismuth compounds have also been found to retard the action

of enzyrne~.~"

Bismuth salts are widely used in the catalysis of organic reactions, such as the

hydrolysis of nbonucleic a d s to dinuclcoside phosphates28sm and the production of

prostaglandins.293

Bismuth(m) has been found to form a saturateci 7:l complex with rat liver

metallothionein (MT), with sirnilar rr~ults for other metal ions, suggeshg linte binding

specificity for bism~th. '~ There has been a debatc over whether the proteins binding

38 bismuth are related to MT, so aitemative terms such as 'hietailothionein-like proteins

(MTP)" and " rend metal binding proteins (RMBP)" have been ~sed.*~' Isolation,

separation and amino acid analysis of these proteins showed that they were different fiom

cadmium induced rat MT.295 These bismuth induced RMBPs in rats have been divided

into two major components which have been studied spectroscopically? The hepatic

protein spectra show preâominantly zinc thiolate transitions, while the m a l protein

transitions c m be accounted for by botb bismuth and copper thiolate binding sites.

2.6.3 Interaction of Bismuth Compoundr wirh Other Dugs and Food

Components

Many studies have been dedicated to detennining the effect of medicinal bismuth

cornpounds on the activity of other medicinal components, or vice versa, in vitro, and in

vivo to evaluate àrug bioavailabilities. Many dmgs have been found to adsorb on

inorganic bismuth salts employed as an tac id^,"^'^*^ while adsorption does not occur

between al1 bismuth sdt-dmg combina t i~ns .~ Other in vitro shidies involve the

adsorption of dia~epaxn,~*' anticoagulantsU# and preservativesw7 on both inorganic and

organic bismuth salts.

Antacid bismuth salts rnay also have an effect on the and

excretion3" of other dmgs in the body when takm concumntly. Bismuth subcarbonate

has been fond to have a variable effect on the antimicmbial activity of various

antibiotics in vitro. 314315 Conversely, biologicdly active molecules may have an effect on

the therapeutic action of bismuth ~al t s ."~ The bioactivity of bismuth compounds

(thiolopnves) is inactivated by molecules containhg thiol groups, such as cysteine,

39 sodium thioglycolate, and sodium thiosuWate, while it is una.Eécted by sulfide and

thioether containing molecules, such as cystine and methionine."' While it has been

reported that penicillin is decomposeâ by bismuth ions in the pmence of water,"' there

were synergistic effécts observed between bismuth compounds and penicillin, which has

no activi ty alone, against T~panosontn equiperdum infectecl

The formation of soluble chelates of bismuth has also been studied in various

drugs and food~.~*' Atomic absorption studies show an enhanceci solubi lity of insoluble

bismuth salts in the presence of certain dmgs and food components including

polyalcohols, hydroxycarboxylic acids, ascorbic acid, aspirin, tetracyclines, vinegars,

h i t and citrus juices3" The effect of the complexation of a variety of antibiotics on the

migration of Bi3+ has been determineci by papa chromatography and

electro~hromatography.~~ Other bismuth-biomolecule solution studies involve

chlorophyll, phe~phytin,'~ D-mannit01~~~ and ascorbic a ~ i d : ~ . " ~ while complexes of

uracil and thiouracil,"' mucate, saccharate and other polyhydr~xcarboxylates~~~ have been

isolated.

2.6.4 Antidotes

Many ligands have ais0 been used as antedotes for bismuth poisoning. Chelating

ligands such as British anti-Lewisite ( H m (2,3-dimercaptopropanol),

ethylenediarninetetraacetic acid (H,edta), paminobcnzoic acidJg and cystine3" offer

some degree of protection against common medicinal bismuth compounds. Mucin

solutions have been suggested as a possible antidote aAcr ingestion of toxic metal

compounds as mucin solutions precipitate the metals h m suspensions of BiOHCO, or

British anti-lewisite (H3m other metals at low pH.''' A series of dithiol ethm have bcen synthesized as chelators

for heavy rnetals, fonning complexes of lower to~ic i ty .~ '~ British anti-lewisite has been

found to chelate bismuth strongly mough to react with bismuth ~ulfide,"~ while studies

of bismuth-u compounds involve stability rneasurements in cornparison to other dithiol

ligands3" and employ polarography."' FuRher, Bi-~dta"~ and Bi-bis! complexes337 have

also been assessed for antimicrobial activity in vitro and in

2.7 Conclusioas

The vast array of medicinal or anti-microbial uses for bismuth compounds

indicates a diverse biorelevance for the element, which is likely valid, but has not yet

been unequivocally demonstrated. A wide selection of compounds and complexes of

bismuth have been investigated for potential bioactivity without justification other than

bismuth content. Some therapeutic utility is best described as 'suggested', and most

experimental studies are impeded by the chernical complexity of the bismuth compound

or the superficial chernical knowledge base that is currently available for bismuth. Most

importantly, few definitive identifications of bio-bismuth interactions have been reported.

Nevertheless, the unquestionable antirnicrobial activity of some bismuth compounds at

low concentrations, the relatively low elemental human ce11 cytotoxicity, and the il1

defined gastric cytoprotective properties of certain bismuth salts highlights the chemistry

41 of bismuth as an important focus for the development or discovery of new phannaceuticai

agents. The efficiency of such developments will depend on the systematic assessrnent of

bismuth chemistry as a foundation for understanding biochemical interactions.

42 Chapter 3. Toward the GeneraI Syathesis of Bismuth Dicarboxylates and the

Structural Cbaracterization of Bismuth Oxalate

3.1 Introduction

As discussed in Chapter 2, emphasis in medichal bismuth chemistry has been

placed on bismuth salts of carboxylic acids and hydroxycarboxylic acids, of which

colIoidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS) are the most obvious

examples. However, the characterization of bismuth carboxylates is hindered by their

hydrolytic in~tability,~' the lability of the ligands in solution and the consequential

sensitivity of the conditions for isolation of solids. Also, the ability of the carboxylate

functional group to achieve extensive intemolecular contacts is responsible for complex

structures in the solid state and likely in solution. The medicinal importance of bismuth

carboxylates has prompted extensive studies of complexes involving simpler ligands

including lactate161, tartrate"*"' and malate'w, al1 of which have been characterized by X-

ray crystallography. Although the solid state structures of the simplest bismuth

monocarboxylates (i.e. formate, acetate) have been detennined, bismuth oxalate (the

simplest dicarboxylate) has only been superficiaily characterized as a guanidinium sait?'

This chapter out lines approaches to minimiMg hydrol ysis and enabling isolation

of bismuth complexes of simple carboxylate ligands. These developments have led to the

isolation of the parent oxalate salt, which has been structurally characterized as bismuth

oxalate octahydrate 36. Section 3.2 provides an overvicw of the data available for mono-

and dicarboxylate complexes of bismuth.

43 3.2 Syntbesis and Structure of Bismuth Carborylatcs

Characterization data for both carboxylate and dicarboxylate compounds of bismuth

are contained in Table 3.1, followed by reaction equaîions for synthetic procedures. Yields

are typically not reported and fonnuiae assignments are based on single aystal X-ray

difkxtion studies. Most compounds sublime rather than meit, therefore rneasurement of

sublimation point (sp) is indicated. Therc are examples of formally molecular and anionic

species and Lewis base adducts (e.g. 301,313 and 317, ncspectively), as well as an example

of a mixed alkoxiddcarboxylate complex (318). Structural details are iilustrated below.

Bismuth carboxylates are typicaiiy prepared by reaction of a basic inorganic

bismuth compound with concentmted carboxylic acid under reflux conditions, while the

anhydride is often introduced to remove by-product water. These compounds may also be

prepared by similar reactions with BiPh,, while partial metatheses give organo bismuth

carboxylates. Ligand exchange reactions with bismuth acetate (reaction 3.2), in particular,

have been extensively utilized to prepare a series of bismuth tris(monocarùoxy1ate) species

301 and 3 0 3 - 3 1 0 . ~ ' " ~ ~ The synthesis of w i (CF ,Cûû) , 1 312= (reaction 3.6) is unique

in that it involves the reduction of pentavaient bismuth. The two thiourea adducts of

bismuth acetate ~i,(CH3C00),&&(HZ0)] 316 and (Bi(CH3Cûû),@g)3] 317 are prepared

fiom similar reactants under different isolation conditions. The favorable

hydrolysis of bismuth carboxylates d o w s for the preparation of the acetate oxide or

"subWacetate [BiO(CH3C00)] 319 by dilution of a solution of Bi20, in acetic acid and

distillation of the excess acid? Other "sub" carboxylates, including [BiO(RCOO)] (R =

44 Table 3.1 Analytical dah for carboxylatc and dichxylate compounds.

1 R A

[ s i ( O P ) J 301 34 l.M3,M7 100(1,2) x x x x x - - X

[si(CH3COJ3 ] 302"'Z"3" 90-95 x x x x x - - x (1 93-51

[si(CD3COa3] 3o2dgW - (1) O - - X - - - [Bi(02CCH2CH3)3] 3OJM1 lOO(2) - x x x x - - x

pi(OzCCH2CH2CH3)3 ] 304"' lOO(2) - x x x x x - x

[C(N&hI [Bi2WCM 32p2** x

[siO,hthd)(OH)] 321 '~ 97(11) - x - x - - - ** The original report codd not be obtained. Crystallo-bic infornation was extracted

f?om Chernicol Abstracts and the Cambridge Crystallogtaphic Database.

*Svntheses:

3.1) Bi203 + 6 RCOOH + 2 Bi(RCûO)3 + 3 H20

3.2) Bi(CH,COO), + 3 RCOOH + Bi(RC00)3 + 3 CH3COOH

3.3) %&O3 + 4 RCOOH + RC(O)OC(O)R + 2 Bi(RCOO), + 2 H20

3.4) Bi203 + 3 RC(O)OC(O)R + 2 Bî(RCOO)3

3.5) Bi(N0,)3eSH20 + 5 RC(O)OC(O)R + Bi(RCOO)3 + 7 RCOOH

+ 3 HNO,

3.6) BiCI, + 3 Ag-) + Bi(RC00h + 3 &Cl

3.7) NaBiO, + 2 RC(O)OC(O)R + N@i(RCOo),J + % 4 3.8) B i . & + 5 RCOOH + 2 L -B [H,LJ[Bi(RCOO)J + 3 P M

3.9) Bi(RCOO), + n L + RCOOH + Bi(RCOO),L, + RCOOH

3.10) Bi(RCOO), + HL + [Bi(RCOO)2(L)] + RCOOH

3.1 1) &O3 + 2 R(COOH), + 2 Bi {R(COO&)OH +

H, C2H9 C,H,, C4HJ9 were reportdy prepared by similar me?hods9 but are poorly

characterized. Pmliminary X-ray structural data was obtained for 319. An attempt to

prepare an O,O%iibe~lzoic acid analogue of [ B i M O H ) J 321 "' by a similar metbod

3.2.1 Catbonyiates

Bismuth foxmate Pi(OOCH),] 3 0 1 ~ ' ~ ~ ' shows monodentate fomate groups at

three different Bi-O distance ranges [avg. 2.38.2.52, and 2.77A 1, alI of which bridge to

neighbouring bismuth centers. The central bismuth atoms are nine-coordinate within

tricapped trigonal pnsms, which share basai tnanguiar faces and fomi a three-dimensional

network through bridging formate groups. Bismutho acctate [Bi(CH,COO), J 3 0 2 ~ ' ~ " ~

shows the bismuth center asymmetrically chelated by Uvce acetate groups pi -O 2.25(2)-

302

2.62(2)A]. Thrce oxygen atoms of two neighbouring complexes (O' and On; 0"') bridge

bismuth centers pi-O 2.8 l(2)-2.94( 1 )A] fonning a layemd structure and a nine-coordinate

environment for bismuth. Bismuth 2 J-dimethylpropioaate [Bi(02CCMe& J, 308Y'15' is

tetrameric in the solid state, with bismuth in a distorted nine coordinate environment. The

coordination sphere contains six ligands bound in various modes: monodentate and bndging

[avg. Bi-O 2.87-3.27A~; O,O'-chelating and non-bridging (avg. Bi-O 2.24 and 2.50Aj; and

0,Okhelating and bridging [avg. Bi-O 2.25-2.73A~. The tetramerie structure shows less

intermoIecular contacts than the threedimcnsional h e w o r k of the formate 301 or the

Iayered framework of the acetate 302, so that 308 is much more volatile at lower

temperatures In addition, the relatively pa ter thmal and hydrolytic stability of the

compound is accredited to the protection of the Rlaive sites by the buiky ligand.

@------Bi------

47 Bismuth benmate pi(C&C00),] 3 1 p shows a similar nine-cwrdinate

environment, however intemolecuiar contacts create a one-dimensional polyrner. The

bismuth center is asymmetricalîy chelated by three benzoate Ligands, fomiing four-

membered -BiOCO- rings. One oxygen atom of each ligand bridges to another bismuth

center pi-0- 2.198(14)-2.533(16); B i - 4 b , 2.243(14)-2.793(18)A] and in tum

each bismuth center meives a long contact ficm three Ligand oxygen atoms [Bi-O

2.624(l6)-~.380(16)AJ.

Neutra1 [Bi(CF3C00), J 31 1 monoanionic [NaBi(CF,COO),] 3 12~ ' and the

dianionic [H2teed]Pi(O2CCFJs] 3133n trifluornacetates have k e n prepared, as well as a

dianionic pentakis(f0nnate) cornplex K2[Bi(OOCH)5 J 3 14. '~ [Bi(CF,COû),] 3 1 1 is very

moisture sensitive, and a stnicture in which the three trifluoroacetate ligands are bound

monodentate to the bismuth atom is suggested based on i n h e d data However, high

melting points and IR data suggest significant molecular associations via bridging

tri fluoroacetate groups. The monomeric anion of 31 3 shows bismuth in a symmetnc ten

coordinate bonding environment, occupieû by five 0,O '-bidentate trifiuoroacetate groups

pi-O 2.44(3)-2.62(2)A]. The distorted pentagonai prismatic geometry can be simpli fied

48 to distorted trigonal bipyramidal if each carboxylate group is considenxi to occupy a single

coordination site. A similar ten coordinate structure is observed for 314.

The trifluoroacetic acid dduct [Bi(00CF3)3(HOOCF,)] 31S3" shows bismuth

bound to three asymmetricaily chelaîed 0,O'trifiuoroacetate groups pi-O, 2.26(3)-

2.27(3); Bi-O, 2.64(3)-2.9 1 (3)A], with the three shortcr Bi-O bond distances in a facial

arrangement, and a monodentate O-ûifluoroacetic acid ligand pi-O 2-71 (3)A]. A long Bi-

-O contact to and b m cach of two neighbouring molecules pi-O 2.79(3)-2.84(3)A]

creates a polymeric chah structure and gives an imgular nine coordinate geometry for

bismuth.

The thiourea adduct ~i,(CH3Cûû),COù,(H20)] 316'" is composed of dimenc

[Bi,(CH,COO), 1" anions and dimeric [Bi2(CH3COO)&) J2+ cations. The eight coordinate

bismuth center of the cation is bound by two bidentate acetate ligands mi-O 2.3 l(1)-

2.7 1 (2)A], three S-thiowea molecules [Bi4 2.677(5) and 3.1 ~ î (6 )A ] and a long thiourea

suifur contact h m a neighbouring group [Bi-S 2.909(5)A]. In the anion, bismuth is nine-

coordinate with four bidentate acetate oxygen groups [Bi-O 2.2~1)-2.78(1)A] and a long

acetate oxygen contact h m neighbouring monomer pi-O

(cation) (anion)

317

49 2.77(2)A]. The adduct pi(CH,C00)3@)3] 3 1 7 ~ ~ is composeâ of monomeric units, with

three 0,O'-bidentate acetate groups [avg. Bi-O 2.509(4)A] and th- fac thiourea d f u r

atoms [avg. Bi-S 3.06 1 (ZIA] in the bismuth coordination sphere. If each bidmtate acetate

group is considerrd to occupy one site, the ninecoordinate geometry may be reduced to

near octahedral.

In the dinuclear mixed a c e t a t e - u [1,3-bi~ethylarnin0)-2-propanolato]

complex ~ i ( 0 0 C C H 3 ) 2 ~ a ~ ) ] , [ H , 0 1 31en two bismuth atoms are bridged by the two

aminoalkoxide ligands p i - O 2.1 8(2)-2.4 l(2); Bi-N 2.68(2)-2.76(3)A]. In this instance, one

bismuth center is asymrnetrically chelated by two acetate Ligands [Bi-O 2.32(2)-2.91(3)A],

while the introduction of the water molecde [Bi-O 2.75(2)A] into the coordination sphere

of the second, and the monodentate bonding of an acetate gmup [Bi-O,, 2.48(2); Bi-O,

2.42(2) and 2.45(2)A], allows for retention of the eight coordinate environment for both

metal centers.

3.2.2 Dicarbo.qvZates

A comprehensive search of bismuth oxalate compounds unvcïled several

13o.3~9~60 nonhydrated and hydrated bismuth oxalate Pi,@zr)II6' and Bi2@LCh~nH,0

(n = 5,6, 7,'M3"8)3a]; ionic complexes [LiBi@a)pnH20 (n = 2, NaBim,*nH20

(NH,),Bi2(&F@2H20 and (NH,),~i,@rù~Cl@8~~0~~~]; complexes containhg fiee acid

[rn~i,(ox)~*nH~ox~~']; and a "sub"oxa1ate [(BiO)2@Ic)361]. There have been systematic

studies of the effect of the h2-y[Bi3"] ratio, sequeme of addition and st-g time on the

composition of precipitated bismuth oxaiate ptoducts h m aqueous solutions of Bi(N03)3

and H&', K a M 6 , (NH4)s367, N a 3 @ or Li92~.~'" Another solution study of oxalate

complexes involves the determination of stability and solubility constants of the

B i ( C 1 0 , ) 3 - N ~ - H 2 0 system by UV spectroseopy."' Fomulae assignments are typicdly

based on chernical analysis or thermal decomposition &ta.

The only cxystailographically characterized oxalate complex [C(NHJ,]~i,(pr)c13]

320Y2 shows bismuth in a nine-coordinate face cented trigond prismatic environment.

Bridging chlorine atoms form duneric units. A series of organobismuth dicarboxylates has

also been report& which includes the oxalate complex [PhBi@)], and was characterized

by EA and EI-MS.

5 1 The IR spectrum of [ B i w O H ) ] 321~~' indicam an ~symmetricai bidentate

coordination of both carboxylate gmups.

3.3 Results and Discussion

Crystals of bismuth oxalate octahydrate ~ i , ( ~ 0 J 3 ] * 8 H , O a were isolated in

very low yield fiom the reactions of excess oxaiic acid with either bismuth chlonde or

bismuth oxychioride in wata under reflux conditions. As with the syntheses of other

bismuth mono-and dicarboxylates, excess ligand is employed to minimize pH and

decrease the fonnation of insoluble hydrolysis products.

As is typical of bismuth carboxylates, the structure of a is highly coordinated,

with each oxalate ligand bonding in a tetradentate manner and bridging two neighbonng

bismuth atoms, as shown in Figure 3.1. Each of the two unique bismuth atoms is

chelated by three oxalate ligands [Bi-Owh, 2.33(1)-2.60(1)A] in a bidentate -0CCO-

fashion (favorable fiveaianbereâ rings). This is an unusual arrangement in that the

carboxylate functionality typically chelates in an -0CO- manner, but is similar to that of

320. Two water molecule oxygen atoms complete the coordination sphere pi-O,,

2.49(1)-2.~7(2)A], giving a total coordination number of eight. The Ione pair on bismuth

appean to be stereochemically active. The overail result is a complex the-dimensional

polymeric network, as observed for bismuth formate 301 and the

hydroxy/alkoxycarboxylates 20598 discusseâ in Chapter 2. There are four non-bonded

lattice water molecules.

The absence of chlorine in the isolated product is striking (cf.

[C(NHJ3][si,('gg)C13] 320'"). Chlonde ion bon& favorably to bismuth in solution and in

Figure 3.1 Crystallographic view of [Bi,(~0,),]~8H20 u. Selcçted bond leagths [A]:

5 3 the solid state, and is in excess in the preparation of a as shown in the following

proposed reaction quation sequence:

Attempts to isolate products nom reactions involving bismuth nitrate or bismuth oxide

were unsuccess hl. In teactions UivolWig bismuth c hlonde, generation of hydrochloric

acid during the reaction may allow for an effkctive decrease of pH below -1.3 (pK, of

oxalic acid), the approxirnate pH at which bismuth subnitrate crystals have been

i~olated,~' .~~*~' and a minimization of hydrolysis reactions. Also, the increased aqueous

solubility of Bi" in the presence of chloride anion (Chapter 2) may facilitate crystal

growth. The low yield of the isolated product precludes definitive conclusions regarding

the bulk reaction. Nevertheless, the isolation of the parent oxalate is an important

observation.

Interestingly, was also isolated in low yield h m the reaction of BiCI, with

excess glyoxylic acid afkr prolonged exposure to air. Aldehyda may be oxiâized to

carboxylic acids in the presence of mild oxidizing agents, such as Ag20 in basic media

(see equation 3-14)? In this case, the oxidizing agent is presumably 4, which is a

stronger oxidizing agent than BiO' unda acidic conditions (see equations 3.15 and 3.16,

respective1 y).'"

3.14) Ag,O + H,O + 2e- * 2 Ag + 2 OH- (EO M.342V)

3.15) 0, + 4 W + 4e- * 2H,O (EO +1.229V)

glyoxylic acid oxalic acid

Monocarboxylates (e.g. formate 301, acetate 302) have been prepared by

dissolving bismuth oxide in neat or concentrated acid (rraction 3. I ) . ~ ' ~ The liquid state

of these acids at room temperature allows for the essentiai absence of water and higher

isolated yields. Solid acids, such as oxalic acid, require the presence of water as a

reaction medium. This has been circumvented in the preparation of bismuth benzoate

310, which involves ligand exchange of bismuth acetate with molten benzoic acid (mp

1 22.4"C) with distillation of the acetic acid b y-product." High yields are also obtained

in the preparation of inorganic bismuth saîts h m concentrated strong inorganic acids due

to the high acidities (low pH) achieved.

3.4 Conclusions and Future Directions

The preliminary isolation of the parent bismuth oxalate from acid solutions

containing chloride anion illustrates a possible general synthetic route to the synthesis of

bismuth carboxylates. The acidic reaction conditions prevent the formation of polymenc

55 and insoluble bismuth hydrolysis products, while the presence of the chloride anion may

assist in preventing hydrolysis and solubilizing the Bi3+ cation.

Foremost to the continuation of this pmject is a comprehensive assessrnent into

the effect of pH and chlonde ion concentration on the formation of bismuth oxalate and

other dicarboxylates (e.g. rnalonic acià, diglycolic acid and thiodiglycolic acid). This

malonic acid E = O, diglycolic acid = S, thiodigylcolic acid

rnay be achieved through the addition of concentraîed hydrochionc and nitric acid in

various ratios. Lower pH conditions may facilitate the isolation of higha product yields,

while the presence of excess chlonde ion rnay promote the formation of various

chemically interesthg chlonde/carboxylate products. Further, cornparisons to reactions

involving monocarboxylates would provide insight into the importance of the chelate

ability of the ligand in product formation.

The polyprotic nature of lactic, malic and t a M c acids allows for the potential

isolation of a varie@ complexes with bismuth. However, few examples (one or two for

each ligand) have been structurally charactcrizeâ (see Chapta 2) and there have been no

systematic studies exploring sequentiai dcprotonation. Again, the efféet of reaction pH

conditions, Bi3' concentration and chioride ion concentration, as well as the chelate

ability of these hydroxy-carboxylate ligands, on product formation must be deterrnined.

Further, systems involving other medicinally relevant ligands such as salicylic, ciüic and

gallic acid must be examined.

56 In Iight of the prominence of the salicylate ligand in medicai applications of

bismuth, novel appmaches to investigating these complexes are of immense interest. An

alternative to the addition of excess mineral acid to UIcrease solution acidity, salicylic

acid may be derivatized to decrease its inherent pK value. This may be achieved through

the substitution of electron withdrawing groups on the ammatic ring, such as a nitro-

group in thepara position to the carboxylic acid fiinctionality (structure 1) or fluorination

of the aromatic ring (structure II).

Despite over 100 years of existence and rnedicinal utility, the structure of BSS has not yet

been detennined due to the insolubility of the compound. As of yet, only submicroscopic

size crystals have been obtained, which have insufficient dimensions for X-ray diffraction

studies. Three compounds closely related to BSS that have been structurally

charactenzed are bismuth "subnacetate 319," bismuth benzoate 310M and bismuth

thiosalicylate 548.'" however, only a preliminary structure was proposed for the

subacetate. Since the subacetate and the 4'sub"formate, p r q d in the same study,

remain the only bismuth "sub"carboxylates that have been crystallized, a comprehensive

reassessment of these preliminary results and a complete structurai characterization may

provide insight into the structures of this class of compounds and their relationship to the

structures of subnitrates, which also contain a labile anion. Further, the techniques

57 employed to prepare bismuth subacetatc could possibly be applied in prrparing crystals of

the "sub"salicylate, of sufficient size for crystailographic studies and stnictural

characterization. A similar approach may yield isolates of the medicinally relevant and as

of yet not structurally characterized "sub"gal1ate.

5 8 Chapter 4. Aminocarboxylates: New Investigations into the Bi-edta System

Iacluding Isolation of the Fint Cationlc Complcx

4.1 Introduction

H,edta is a strong chelator of most metals including bismuth, and the Bi-edta

system has been extensively studied in the solid state and superficially in solution. The

Bi-edta complex is an analogous polyciuboxylate system to the Bicitrate system and is

more soluble and rigid under various pH conditions, making it an excellent candidate

mode1 for the solution chemistry of CBS.

Polyaminoc~xylates, such as H&Q, are derivatives of a-amino acids, the

building blocks of proteins, and are themselves of biological interest. The cytoprotective

nature of commercial bismuth products is believed to Lie in the abiiity of bismuth to bond to

protein molecules of exposed tissuePa and any chemicai insight into bismuth-

aminocarboxylate systems is therefore of value.

This chapter introduces the established syntheses and structures of bismuth

polyarninocarboxylates, followed by the synthesis and structural characterization of the

first cationic Bi-edta species {Pi(Hedta)Jl,H) Cl.ZH,O a. A preliminary ESI-MS study

of the Bi-edta system, at low and high pH values, is also presented.

4.2 Synthesis and Structure of Bismuth-Aminocrirboxyiatcs

Several examples of bismuth polyambcadmxylatcs have been prepared, the

majority of which arc & complexes. and anploy ligands which possess wide variations in

chelate ability (i.e. number of fiuictional groups). Dcrivatization of more comrnon ligands

involves addition of a cyclohexyl ring to the hydrocarbou backbone (e.g. cvdma) or

substitution of acetate bgments for akoxyethyl p u p s (e.g- oedta). The water solubility

of bismuth polyaminocatboxylates increases with the nurnber of carboxylate groups on the

ligand, thereby facilitating crystai p w t h . However, fields are typically not reported and

studies are comrnoniy basd on single crystal X-ray difnaction studia only.

Characterizaion data for compounds discussed are contaiad in Table 4.1.

Bismuth polyaminocarboxylatcs arc typically prepareâ by heating under reflux a

suspension of a basic inorganic bismuth salt such as Bi,O, Bi(OH), or (BiO),CO, with the

appropriate ligand in water. Addition of base, such as guanidinium carbonate or an alkali

hydroxide, to the reaction mixture affiords the anionic salt in most cases. The neutral

dihydrated Pi(Hedta)(H,O)J 41 lmJX and non-hydrated3" complexes are reportedly

synthesized by analogous reactions involving bismuth subcarbonate and bismuth hydroxide,

respectively, while bismuth nitrilotriacetate dihydrate (Hm Pi&g&(H,O)J 4063753* and

the trihydrated produc?% are also isolateci h r n similar reactions. The trihydrated product

was characterized by elemental analysis and Uifirared spectroscopy only. The dihydrated

Table 4.1 Analytical data for arninocarboxylate compounds.

Compound yield X E 1 U N M T p (nui R A R V M S G o 4.n)* R A t

@~~(~I&(H~O)J 401358 80(1) - x x - - - - - ~i@&)(Hphç)@mso)] 402'" 42) x x - - - - -

~icondg)('H2O)J 403'" 40) x - - - - - O - [NHJ [si(Hond9),(HZo)3~ 4Wa 4-1 X - - - O - - -

~ C ( M I 3 3 l , [ s i ~ ~ 2 0 ) 3 1 4-1 x - - - - - - - 405~'''

60 Table 4.1 Analytical data for aminocarboxylate compouads (continued).

Compound yicld X E 1 U N M T p (nar R A R V M S G O 4.n)* R A t

B i w ( H 2 0 ) 2 ] 4M"' - (3,4) x x - - - - - - W,]JBiQ&J 4O1"lJ8' - (5) r - - - O O - -

~,]4~i(nta)2(NCS)].2H20 40%'~ - (6) X - - - - - - -

[Bi(Hoedta)(H20)] 40937sJu -(1) - x x x - x x

[ N a B i 0 ~ 2 0 ) . 1 41P' -(7) - x - x - x x

pi(Hedta)(H,O)J 41 1 384.385 -(3) x x x - - - - -

mi(H,O)d [si(edta)],.3H20 4 1 7 ~ ~ - (7) x - - - - - - -

~aBi(edta)(H,O), ] 41 - ( i l ) x x - - - X -

[NH41IBiCehtg)(~20)1 4193" -(12) x - - - - - - - [Bi(Hcvdta)(H20),] 420'" -(3) x x x - - - - -

[Bi(H2dtq)(H20)J 421 376.393 47 x x - X X - - (13,141

edta sodium salt ~ i ( e d t p c ~ ~ ~ 0 ) J ~ ~ ~ is reportedly prepared by adding an aqueous NaOH - solution to a suspension of (Bi(Hed@ J, though the compound has not bem

comprehensively characterized. The sodium [Bi(Na&p&@I,O),] 422376 and guanidinium

[C(NH33]2pi(&&(H20),] 423375 salts are preparcd h m the neutral complex 421, and the

high water solubility in cornparison to similar bismuth polycaTbOxy1ates is scmdited to its

anionic nature.

62 Complexes involving && have been most extensively c h a r a ~ t e r i z e d ~ ~ ' ~ ~ ~ and

ùiclude examples of both hydratedZmfu3-' and n~n-hydrated-~-~ pi(Hedta)], as well

as the ~&376.391.W1 K3* NH,:86Jw Mg,"'3 Ca,389" Sr, Ba, Ni, Zn, Cd,"'3 CO:^.*^ Cu" and

Mo3W salts of the pi(edta11- anion, as well as the potassium fluoride complex

several examples of [Bi(Hgdta)] (41 1-13) and pi(edta) J' (41 4-19} complexes.

Aminocarboxylate Ligands typically exhibit maximum chelation with bismuth,

forming five-mernbed -BiNCCN- and/or -BiNCCO- rings. The large covalent radius of

bismuth (1.52A) allows for chelation of Ligands in the bidentate to decadentate range.

Additional coordination sites are typically occupied by oxygen atoms of water molecules or

exocyclic carboxylate oxygen atoms of neighbouring molecules, creating polymenc

structures.

A structure containing three -BiNCCO- five-membered chelate rings has been

proposed for the quinaldic acid (H& complex [Bi@&(H20)J 4013" h m cornparison of

infhred spectra with previously characterized compounds.

The prndine-2,6-dicarboxylic acid (Hm complex [Bi@dçxHl&)(&nso)] 402"'

shows the bismuth center chelated by both an N'û-bidentate (Hmpdç) ligand and an OJV,O'-

tridentate 0'- ligand [Bi-O 2.209(8>2.507(6); Bi-N 2.4 l8(9) and 2.48 1 (9)Al. An O-

dmso molecuie in the remaining axial site mi-O 2.61(1)A] and a long cahxylate oxygen -

63 contact h m a neighbouring molecule [Bi-O 2.578(4)A] create a centrosymmetric dimeric

structure and a seven coordinate distorted pentagonaï bipyramidal geometry for bismuth.

The protonated carboxylate p u p p i -O ~.738(6)A] is not considered to be bonded to

bismuth.

In the neutraJ N-hydroxyethylnitrilodiacetic acid (H30ndq) complex

pi(onda)(HIO)J 40337g the unda)* ligand chelates bismuth in a teûadentate manner p i -N

2.49(2); Bi-0- 2.33(1) and 2.34(1); Bi-0- 2.1ql)Al. A long alkoxide oxygen

(O) contact h m a neighbouring moiecule creates dimers (Bi-O 2.46(1)A], which in turn

are linked by long carboxylate oxygm contacts of other dimers [Bi-O 2.7q1) and 2.98(1 )A]

to foxm a iayered structure. A water molecuie [Bi-O 2.77(2)A] completes the coordination

sphere and gives an eight coordinate distorted bicapped trigona1 prismatic geometry for

64 [C(NHJ3]2[si(~~&.pndgXH20)3] 40sJm also show the (HQ&)'- Ligand chelating in a

tetradentate fashion, despite the lowa basicity of the hydroxy- p u p in cornparison with

the alkoxide.

[Bi(pyg)(H20)J 406'" shows the bismuth center chelated in tetradentate fashion

by one m3- ligand [Bi-N 2.500(8); Bi-OeXyk 2.258(6)-2.253(7)A]. Two

intemolecular contacts pi-O 2.665(6) and 2.435(6)A] h m a neighbouring molecule

create a dimeric unit. The eight coordinate bicapped trigonal prismatic coordination

sphere is completed by the oxygen atorns of two water molecules [Bi-O,, 2.403(6),

2.767(9)A]. The monomeric anion of w,],[Biw4 40738'3" shows bismuth bound in

a tetradentate fashion by two m* ligands mi-N 2.58(1) and 2.60(2); Bi-O 2.44(1) and

B i-O 2.40( 1 )A], gïving a total coordination number of eight for bismuth and a doubly-

capped trigonal pnsm geometry. The structure of the b i s 0 thiocyanate compound

[(NH,),B i ~ , ( N C S ) ( H 2 0 ) J 408382 is andogous Fi-O 2.363(4)-2.5 5 1 (5); Bi-N

2.605(4)A], but also incorporates an N-isothiocyanate ligand mi-N 2.71(1)A] into the

bismuth coordination sphere, giving a nine-coordinate distorted tricapped trigonal pnsm

geometry at bismuth.

65 The whydn,yethylethyl~ediamine~acetic acid (H,oedta) compound

[si(Hoedta)(H,O)] 4w763U and the sodium sait ~aBi(oedt&(HZO),l 41v" have not been

Several bismuth complexes of ethylmediaminetetraacetic acid (H4edti3) have been

studied by X-ray methods~09384389J90*100-~**0i1 and al1 contain a hexadentate (Hedta)3-or

(edta)& ligand. The structure of pi(Hedt&(H20)J d l 13U38S shows the (Hedta]" ligand

[Bi-N 2.396(10) and 2.577(9); Bi-O 2.295(7)-2.7OO(l O)A]. The coordination sphere is

again completed by two carboxylate oxygen atoms of a neighbouring molecule pi---O

2.678(7)- 2.697(8)A], forming a dimer structure. The result is an eight coordinate

bicapped trigonal prism geometry for bismuth? The dehydrated analogue wi(Hedta)]

412"~ pi -N 2.465(5); Bi-O 2.399(3)-2.472(4)A] also shows two long oxygen contacts,

but fiom different neighbouring molecules [Bi--O 2.61 ~(s)AJ. This creates a one-

dimensional polymenc chah arrangement and a distorted square antipnsm geometry at

bismuth. The introduction of thiourea into the coordination sphere [Bi-S 3.03~(4)A] in

66 the adduct [Bi(Hedtg)&)J 413'" [Bi-N 2.5 lû(7); Bi-O 2.378(7) and 2.521 (9)A] prevents

intermolecular coordinations and results in a monomeric structure, bound ody through

hydrogen bonding.

In the [C(NHJ,]pi(edta)(H20)] 414'U anion, bismuth is similarly chelated in a

hexadentate fashion but by (edtaIC pi-N 2.56(1) and 2.59(2); Bi-O 2.34(1)-2.46(1)A].

A long Bi-O contact to and h m two separate neighbouring molecules pi-O

2.70(1)A] forms an &te anionic chain. A bound watcr molecule [Bi-O 2.69(1)A]

gives a total coordination numba of eight for bismuth and a distorted square antipnsm

geometry. nie calcium salt [Ca(H2O),][Bi&&)l2~2H2O 41sJa9 [Bi-N 2.460(6) and

2.543(6); Bi-O 2.360(6)-2.463(7)A] attains a similar polymeric chah structure, however,

the absence of the water molecule in the bismuth coordination sphm allows for a second

Bi---O long contact [Bi-O 2.778(6) and 3.038(ï)A] between monomers. Analogous

structures are observed for the isostruchual transition metal salts

[Co(HzO),] [si(edta)]p3H20 41 6 and [Ni(H,O), ][Bi(edta)]2a3H20 4 1 7.)" The sodium

salt VaBi(edta)(H,O),] 418'~' [Bi-N 2.495(5) and 2.508(5); Bi-O 2.3 IS(4)-2.521(4); Bi--

-0 2.636(4) and 2.850(7)A] and ammonium salt [NII,][Bi(cdta)(H20)] 419''~ [Bi-N

67 2.479(9) and 2.490( 10); Bi-O 2.290(9)-2.494(8); Bi-O 2.792(9) and 2.80~(8)A ] aiso

show two long Bi-O contacts h m two neighbouring monomers, but in these cases a

layered structure is created.

[Bi(Hc~dta)(H~O)~] 42v9 displays a simila. bonding situation to the edta analogue

414 pi -N 2.49 1(11 kî.5 1 3(lO); Bi-O 2.286(9)-2.497(11)& Long Bi-O contacts from

two neighbouring molecuies [Bi-O 2.6 1 2(9)-2.9 1 6( 1 0)A ] mate a polymeric network.

420 (Bi bonding environment)

[Bi(H,dtl,a)(H20)J 421)'~~~ shows the ( ~ d m a ) ~ Ligand chelating in a heptadentate

marner with one uncoordinateà acetate gmup p i -N 2.449(4)-2.723(4)A; Bi-O 2.290(3)-

2.699(3)A]. An eighth coordination site is occupieâ by a long Bi-O contact nom a

neighbouring molecule [Bi-O 2.620(3)A], giving rise to an infinite polymeric c h a i . and a

bicapped tngonal prism environment for bismuth. The guanidiniurn salt

[C(MI3J2Pi(d~a)(H20),] 423" shows that the ligand chelates in an octadentate

manner [Bi-N 2.536(7)-2.639(6); B i 9 2.368(~)-2.599(5)A 1. The coordination spbere is

cornpleted by an oxygen atom h m an adjacent molecule pi-O 2.686(6)A], creating a

dimeric structure and a nineccoordinaie monocappi squm antiprisn environment for

bismuth. The potassium salt [KBi(H&p&(HIO)s] 4 2 P shows a similar octadentate

chelating situation, but with a water oxygen atom completing the coordination sphere and a

monomenc structure.

in [C(NHd3 J2[Bi(cvdtpa) ] 425,'93 0% chelates in an octadentate manner [Bi-N

2.458(5)-2.592(5); Bi-O 2.371(4)-2.610(4)A] giving a monomeric structure. Here, bismuth

is in an eight coordinate environment, which may be daiveà h m a square antiprism.

425 (Bi bonding environment)

pi(H$tha3(H2O), ] 426" shows the (Hm3- ligand chelatuig in a ddentate

manner [Bi-N 2.472(8)2.8 1 3(8); Bi-O 2.320(7)-3.0~~(8)A]. The coordination geometxy

around bismuth may be descnbed as distorted bicapped square antiprism, with the two

extemai nitrogen atoms QU' and N') in capping positions. This is the fht example of a

426 427 (Bi bonding environment)

polyarninocarboxylate complex with coordination numôer ten. The bis(guanicîinium) salt

[ C ( N H J J J B i ( H O ) , ] 42y3* shows (HmE chelating in only a nonadentate manner,

wi th one noncoordinated carboxylic acid group (0') p i - N 2.6 19(7)-2.688(7); Bi-O

2.327(6)-2.560(6)A].

4.3 Results and Discussion

4.3.1 Synthetic Studies

H ydrogen bis(bisrnuth hydrogen N&flJv'-ethylenaiiamllietetraacetate) chloride

dihydrate {[Bi(Hgdt;i)J2H)CI@2H,0 a (Figure 4.1) is formed h m the stoichiometric

reaction of H,edta and b i s m u t h o chloride in water with addition of KOH. ïhe

isolation of the product h m reaction mixtures containhg 1-4 equivalents of KOH

demonstrates the favorabie crystdlization of this stnicture and the msistance of the Bi-

edta hexaadentate unit to small pH changes. However, reactions involving 0.5 and 5 - equivalents of base gave non-crystalline materials, which were not dennitively

Figure 4.1 Crystallographic view of {Pi(H&&H} C1*2H20 a.

7 1 charactenzed but were determined by Raman spectroscopy not to be the said product.

Reactions of bismuth subcarbonate t y p i d y yield the pi(H&t@] hydrated species, while

addition of a strong base such as guanidinim carbonate gives deprotonated anionic

species. The favorable crystallization of the cationic cornplex 46 is possibly a

consequence of the presence of the chioride anion.

The solid state structure of (see Figure 4.1) shows edta bonding to bismuth in

the familiar hexadentate manner. The absence of chlorine or water or long (Bi-O)

intermolecular contacts results in unusually low coordination number of six for bismuth.

Two neighboring Bi(Hedta)] units are bound at 0(6) to a common hydrogen atom

(proton). This hydrogen bonding phenornenon is characteristic of metal-

polyaminocarboxylate complexes and has bcen dubbed the "odd proton e f f e ~ t " , ~ with

two of the three examples of complexes involving ( H m L exhibiting this feature. In the

case of [Bi(Hedt@] 412 and the thiowa adduct 413,'" the "odd-proton" occupies an

inversion center and each molecule contains two "half-protonated" carboxylate groups,

resulting in the formation of hydrogen bound chahs. schematically represented by III.

The dihydrate 41 1 exhibits a specific location for the proton on a single carboxylate

group, which is hydrogen bound to a water molecule and terminates the system (see

diagram IV). For compound q& the odd-proton is located on a C, axis between two

Bi(Hedta) uni& without fiirther perpetuation, md a fblly pmtonatcd carboxylate group is

expected for each rnoiety of the cationic dinuclear unit (see diagram V), such as that

III IV

observed for 41 1.

X-ray crystallographic daîa suggests that the proton exclusive to each

mononuclear unit is bound at the exocyclic carboxylate oxygen O(2) and not the water

molecule, though this codd not be determincd with certainty. The C-O bond lengths may

be examined for clues to identify the remaining protonated p u p s (Table 4.2). For

[Bi-)(H,O)J 41 1,'"'" the position of the hydrogen atom was inferred nom the

equivaience of the carbon-oxygen bond distances of the three deprotonated carboxylate

groups, which is interpreted as conjugation of the double bond after deprotonation, and

the nonequivalence of those in the fourth carboxylate group. No such conjugation is

observed in 9& however, with the C-O bond distance discrepancy being -0.04A for three

carboxylate groups and -0.06A for the fourth [C(6) 1. Further, of the carboxylate groups

in question, bond distances suggest greater double bond character (Le. shorter bond

distances) for al1 exocyclic oxygen atoms. In both fi and 411 the bismuth center sits

asymmetncally in the O,N, cavity and is more closely bound to three carboxyl oxygen

atoms and one nitrogm atom. In the case of 41 1, the carboxylic acid group is tightly

bound to the bismuth center, and thmforc is not an indicator as to which group is

protonated. From a chernical standpoint, a hydmgen atom at 0(2) would allow for

hydrogen bonding of the chlorine atom to the ligand and is therefore a logical site for

the proton.

7 3 Table 4.2 Selected bond lengths for [Bi(H&&] complexes.

As discussed in Chaptm 2 and 3, the hydrolysis of Bi3+ to BiO' in al1 but strongly

acidic conditions typically deters the formation of soluble bismuth tris(carboxy1ates) in

aqueous media The significance of pK, in the preparation of arninocarboxylates has

been alluded to as the pretense for the failed isolation of a bismuth picolinic or dipicolinic

acid complex (i.e. pK, of -5 is too weak to react with bismuth subcarbonate), and in light

of the successfûl preparation of atê, edta and a complexes by similar methods.'"

However, the dipicolinic acid d m s ~ adduct 402 was successfilly prepared fiom the

reaction of the acid and Bi,03 in water, followed by fiirther reaction and recrystallization

of the resulting powder fiom hot ~. This suggests that reaction in &so is critical to

isolation of the product, and the absence of excess water at this stage may allow for

product formation. Further, the stmng Lewis base character of dm=, which foms

resilient complexes with bismuth, may aid in solvation of the ~ i ' + cation. Although

74 ligand pK, (pH of &on mixtures) does play a role, the strong chelate ability of

polyaminocarboxylates is most Uely the dominant factor in the formation and stability of

these compounds. The multidentate encapsulation of the bismuth center prevents

formation of the Biot bismuthyl ion in water. Thcrefore, bismuth complexes of bio-

relevant a-amino acids, which possess high pK, vaiues relative to monocarboxylates (9.6

for glycine venus 4.7 for acetic acid) and the ability for bidentate chelation only, may not

be prepared b m aqueous media Hydroxy-/alkoxycarboxylates, such as lactic, malic,

tartaric and citric (CBS) acids are much weaker chelators for bismuth and complexation

is expected to be much more sensitive to pH [e.g. citrate (CBS) requires an alkaline pH].

Only a small number of structures of this class of compound have been reported

exclusively within the past decade.

4.3.2 Preliminury Electrospray M a s Spectrometty Studies of the Bi-edtu System

Bismuth complexes are typically v a y insoluble and are subject to hydrolytic

reactions. Collection of solution data thmfore oAm requires sensitive techniques which

lend themselves to nonspecific experimental conditions. Aithough Bi-carboxylate

solution complexes have been examineci by a variety of physical and spectroscopie

techniques, none of these provide definitive formulae or structurai data Electrospray

mass spectrometry @SI-MS) involves the introduction of prc-fonned ions in solution into

the mass spectrometer. The subsquent scparation of ions accordhg to their mass to

charge ratio, as well as their controllcd fragmentation, provides ample information as to

the identity of solution species.

Bismuth complexes of citrate are complex in the solid state, while the

multidentate encapsulation of bismutth by & d o w s for the formation of simpler

pi(Hedtaj] and Pi(edta)Ja units. This, dong with the similar polycarboxylate structure

of the two ligands, highhghts the Bi-giQ system as a simple mode1 for studying the

solution chemistry of the Bititrate system and Bi-carboxylate systems in general.

Preliminary positive ion ESI-MS spectraa of the Bi-edta complex at low pH (1.4)

show peaks at mlz 499 (100% ml. htcii~ity) and m/z 293 (95% rel. intensity) assigned to

the [Bi(Hzedta)]' and [Hsedta]+ cationic species, respectively. At high pH (10.0), the

negative ion spectnim shows a peak at mlz 497 (100% rel. intensity) assigned to the

pi(edta)]- anion. These results contrast speculative conclusions based on

spectmphotometric and pH metric data that ouggcsts the decomposition of the complex to

the bismuthyl ion (Bi03 below pH 1.5 and the fornation of ~i(edtgKOH)]*- in the pH

range 8- 1 1 .'"

4.4 Conclusions and Future Directions

The strong chelate ability of polyaminocarboxylate ligands allows for the

formation of hydrolytically stable complexes with bismuth, while bifùnctional

aminocarboxylate ligands (e.g. glycine) p o s ~ s s insufficieut acidity or chelate ability to

deter hydrol ytic reactions. Investigation into scquential protonation of bismuth

polycarboxylates may provide fiirther insight into the significance of pH and chelate ability

on product formation. Further, prcliminary investigations demonstrate the inherent utility

of ESI-MS to study Bi-carboxylate systems in solution, which may be developed to

investigate the solution chernistry of CBS and other bismuth carboxylates and the

resilience of dirneric and polymeric associations observed in the solid state.

Reaction of a-amino acids with bismuth salts under anhydrous conditions would

eliminate the possibility for hydrolysis reactions associated with this system. This

method has been employed successfully in the synihesis of an organobismuth complex of

N-benzoylglycinate'"' and is a viable appmach to preparing other stable amino acid

complexes of bismuth?

As with the study of bismuth complexes of a-amino acids, investigations

involving di- and tripeptides would provide insight into bismuth-protein binding at ulcers

and throughout the body. Further, the variety of fiinctionalities associated with

polypeptides creates the potential for intmsting bonding situations. The only recent or

s igni ficant study that has been undertaken involves the tripeptide glutathione and

ranitidine bismuth citrate (RBC).~'* The thiolate (sulfhydryl) functionality was proposed

as the only site of binding by 'H NMR, but structural data could not be obtained.

Reaction of glutathione with simpler bismuth starting materials (e.g bismuth halides) in a

variety of pH conditions and solvents rnay allow for the isolation of chemically and

structural1 y interesthg produc ts.

The insolubility of bismuth subsalicylate has preveuted its structural

charactenzation to date, and the favorable hydrolysis of bismuth salicylate compounds

may be observed as a consequence of the weak chelate ability of the salicylate ion.

Derivatization of the ligand to include additional carboxylate gmups would incnase the

chelate ability of this ligand (cf polyaminocYboxylates), possibly allowing for the

formation of hydrolyticaliy resistant and soluble products. Potential avenues of

77 derivat ization include addition of carboxylate groups to the salicylate phmyl ring (e-g.

structure VI) or combination of two (e.g. structure WI) or more (e.g. stnicture WII)

carboxylate moieties:

Mn

As discussed in Chapter 2. the speciation of Bi3' in acidic media is still a matter of

debate."gs ESI-MS, which now has a demonstrated utility for Bi-ecita species in solution,

may also prove advantageous over previously ernployed methods (e-g

spectrophotometry. 209-2 13 and 2m21spotentiometicm7) in the definitive identification of both

positive ion and negative ion species prcformed in solution.

Cbnpter 5. In!roduction to Bismuth Thiolate Chembby

5.1 Introduction

The prominent thiophilicity (the preference to foxm bonds to sulfùr) of bismuth is

responsible for the facile formation of sulfido and thiolato complexes, which are well

established for most heavy metal elementsm niid atobismuth complexes represent the

most extensive class of B i 0 compounds for which a reliable set of data is available,

and include examples of monothiolates, dithiolates and bifunctional ligands incorporating

a thiolate group, as well as thio-substituted carboxylates. This chapter is provided as an

introduction to the synthetic and structural chemistry of bismuth thiolates and as a

background to the bihinctional thiolate chemistry discussed in Chapters 6 and 7 (for a

more detailed and generai overview of the structurai features for bismuth complexes

involving pnictogen and chalcogen donon see reference 410). A summary and

conclusions regarding the extensive data presented is provided in section S.S.

5.2 Monothiolates

Despite an extensive history, most examples of bismuth thiolates are poorly

charactenzed, with the f h t structurai studies of the more stable and soluble arythiolates

occwing within the past decade.'" Characterization data for bismuth-thiolate

compounds are catalogueci in Table 5.1.

Bismuth thiolates are typically prepared by reaction of the thiolate anion

(generated in situ) with a bismuth salt, however, the thiol will also react with bismuth

Table 5.1 Analytical chia for monothiolate compounds.

Compound yield X m E s 1 U N M T ( m 5 . n ) + R p A O R V M S G

1 R A Bi(SEt), 501'" - (1) - x - - - - - O -

Bi@%), 5024'3"'4 lOo(2) - x x 0 x - x x -

Bi(SCH,Ph), 5034'"4" 61 (3), 72 - x - - x x x - x (4)

Bi(SPh), 5044""'6 79(1) x x x x x - - - x

*Svntheses:

5.1) Bi(NO,), + 3 RSH + Bi(SR), + 3 HNO,

5.2) BiF, + 3 MqSiSR -* Bi(SR), + 3 MqSiF

5.3) BiCl, + 3 MSR + %i(SR), + 3 MC1

5.4) BiCl, + 3 RSH + NEt, + Bi(SR), + 3 NEt4Cl

5.5) Bi[N(SiMe& + 3 RSH + Bi(SR), + 3 m ( S M % ) z

5.6) BiPh, + 3 RSH + Bi(SR), + 3 PhH

5.7) &(SR), + L + Bi(SR),L

5.8) Bi(SR), + W(lB-crown-6)]SCN + [K(18-crownd)]~i(SR),NCS]

nitrate or triphenylbismuth to give the thiolate product. Other metathesis reactions

involve silylamine and silylsulfide reactants.

The pentafiuorinated aryl derivative Bi(SC$;), 51 24'6"'7"20 is prepared fiom the

reaction of the thiol with the bismuth cation in water or weakly acidic solution, or with

BiPh, under reflux conditions, while the reaction of BiCl, with three equivalents of the

thiolate results in the formation of the pentathiolate dianion ~a&f'),]~i(SC$,), ] 513,

instead of the tris(thio1ate) 512. The excessive thiolation of bismuth may be accredited ta

the increase in Lewis acidity of the bismuth centa resulting h m the electron withdrawing

influence of the fluorinated ligands. Additionaily, the greater nucloophilicity of the thiolate

overcomes the kinetic barrier.

The earliest reporteci bismuth thiolates arc those of simple akyl thiolates, such as

tris(ethylthio1ato)bismuth 501 :12 which are relatively rcactive compared to other bismuth

thiolates. Bi(S'Bu), 502 is stable under vacuum, but dccomposes in air and in

dichloromethane solution while Bi(SCH2Ph), 503 is îight smsitive."' Themolysis of

503 and the unsubstituted phenylthiolate compound Bi(SPh), 5044'5"'6 compound results

8 1 in the formation of bismuth metal, Bi& andlor disulfide~.~" The sterïcally encumbered

arylthiolate compounds Bi(SC&R',-2,4,6), 508-510~"*~" are air stable, sublime under

reduced pressures and are soluble in many organic solvents, while solutions oxidke to the

aryl disulfides.

The tns(alky1thiolate) Bi(S'Bu), 502 was determined to be monomdc in the gas

phase fiom mass spectrometry data, while its monomeric nature in the solid state is

inferred from cornparison of infrarrd data with that of the arsenic and antimony

analogues."'

The solubility of the unsubstituted tris(arylthio1ate) compound Bi(SPh), 504 4'5.4'6

in weakly donating organic solvents suggests a monomeric or weakly polymenc

structure, while preliminary X-ray analysis data suggest the compound has a similar

structure to 510.'16 The substituteà arylthiolate B ~ ( S C & B U , - ~ , ~ , ~ ) ~ 5 1 0 ~ " ~ ~ " shows

discrete monomers in the solid state, which is edorced by the steric buk of the ligand.

The bismuth center is in a three coordinate pyramidal environment [S-Bi-S 90.3(2)-

1 04.5(2)O] with identicai Bi-S bond distances mi-S 2.554(7)-2.569(8)A].

510

The pentafiuorinated aryl derivative Bi(SC&)3 512416-4'7~420 pi-S 2.532(2)-

2.584(2)A] shows a loosely bound dimeric unit in the solid state via a longer bndging

512 513

sulfûr contact pi-S, 3.323(2)A], with bismuth in a four coordinate disphenoidal

bonding environmat."" The dimerization of SlZ as compareci to 510 is presumably a

result of the l e s sterically bdky ligand. The structure of the anion [Bi(SC>J512- 513 shows

bismuth bonded to five pentafiuorothiolate ligands in a square pyramidal geometry Bi-

s,& 2.988(9). 2.703(9), 2.889(9) and î.W6(lO); Bi-S,, 2.609(10)A]. nie rernaining

apical site is occupied by a long intramolecular bismuth fluorine contact [Bi-F 2.94Al.

The incfeased Lewis acidity of the bisnuth center of 512 allows for preparation of a

number of Lewis base adducts [Bi(SC&(L) including examples of mono- (514 and

SIS), bis- (51 6-51 9) and tris- (520) adducts, and the anionic thiocyanate mono-adduct

~(I~-C~OWII-~)J~~(SC~~)~(NCS)] (521). AU structures are based on an octahedral

geomeûy and contain a pyramidal Bis, unit. A tram influence is observeci in al1 cases in

that introduction of Lewis base donors effects significantly longer Bi-S bond distances in

tram positions. The structure of mono- adduct 514 (L = SPPh,) shows the compound as a

centrosymmeeic dimer in the solid state, with bismuth in a five coordinate square

pyramidal geometry [Bi-Su 2.57(1)-2.62(2); Bi-S- 3 .O 1 (1)A] and involving a single

long contact h m a bridging suifur of the neighboring molccuie [Bi-S 3.1 S( 1 )A]. A

simila, structure is obsewcd for bismuth in the 521 anion [Bi(SC&),(NCS)]- pi-S,,

2.645(2), 2.2.6 14(2), 2.564(2)A]. in tbis case, the isottiiocyanate ligand bridges in an

-NCS- manner, and is more tightly held to the monomer through the nitmgen atom [Bi-N

2.577(6); Bi-S 3.178(2)A]. The bis- adducts 516518 (L = OPPh,, j m ~ a and DU>

respectively) show similar structures but are now monomeric [Bi-S- 2.548(2)-2.588(2);

Bi-SqM î.S74(2)-2.670( 1); Bi-O 2.502(3)-2.728(5); Bi-F,, 3.102(6)-3.254(7)A]. nie

structure of the tris- adduct 520 CL = SC(NHMe)J is similar to the bis- adducts, but

incorporates a third S-donor ligand into the maining axial site, creating a six cwrdinate

near octahedral environment for bismuth (Bi-S, 2.721(2); Bi-S, 2.946(3)A].

It is clear h m these structural obsavations that there is a tendency toward a

pyramidal facial arrangement for the Bis, unit of 512. Secondary bonding characteristics

are similar to that of the bismuth tribalides in the accommodation of one to three Lewis

base ligands, while the steric buk of the pcntafluorothioph~11olate ligand is s a c i e n t to

prevent the polymerization observed in mono- and bis- ligand complexes of bismuth

trihalides and phenyl dihaIidesYe6 These observai octahedral-based geometries and

84 tram effects are consistent with a mode1 involving B i4 a* acceptor orbitals, discussed

firîher in Chapter 7.3.

5.3 Bifunctional Thiolates

Several examples of bismuth complexes of bihctional ligands incorporating one

or two thiolate groups have been prepad. With the exception of the dithiolate species,

the increased solubility of these complexes (se Chapter 6) has allowed for more

extensive structural studies, particularly in the case of hydroxyethanethiolates.

Characterization data for these compounds is catalogued in Tables 5.2-5 .S.

Table 5.2 Analytical data for dithiolate compounds.

Compound yield X m E c 1 R M p (rxn5.n). R p A O R a S O

n m 1 [Bi (S(CHJ,S) CI] 52f"' 82(9) - x x - x x x -

522e2pyL12s 85(10) x x x - - - - -

[Bi {S(CHJ,S} Cl] 52J2 95(9) - x x - x x x - pi {S(CHJ4S) Cl] 524' 97(9) - x x - x x x -

[Bi {S(CH,)2S(CH~2S J CI] S2SL4- 87(9) r x x - x x x - [Bi {S(CH3,0(CH~,S}CI] 526Z4m 6@92(9) x x x - x x x -

{s(mJ~Ss) 31 527' 97(11) r x x - x x x - IB iz {S(CH2hS) 31 5282 92(11) - x x - x x x -

85 Table 5.2 Analytical data for dithiolatc compounds (continuai).

Compound yield X m E c I R M p (rxnS.n)* R p A O R a S O

~i2{S(CH~20(CH~2S)3]5312 99(11) - x x - x x x - mi {S(CHa2S} Br] ~ 3 2 ~ ' ~ %(9) - x x - x - - -

- -

~ 2 a 2 p r ~ ~ ~ 93(10) - x x - - - - - p i ( 3 ,4-S2CJr3Me)C1] ~ 3 3 ~ ~ ~ 84 (9) x x - - - - -

*Svntheses:

5.9) BiX, + HSRSH + Bi(SRS) + 2 HX

5.10) Bi(SRS)X + n L + [Bi(SRS)X]L,

5.1 1) 2 Bi(NO,), + 3HSRSH + Bi2(SRS)3 + 6 HNO,

5.12) m BiX3 + n NaSRSNa + s m ] C l + mJ,[Bi,(SRS)JJ + s NaCl

+ (3m-t) NaX

527 528 529 530 531

aqueous NaNQ solution. The sodium nitrate presumably promotes heterolytic Bi-Cl

bond cleavage, while the tethering illustrates the thermodynamic preference for the Bi-S

bond formation.

In addition to spectroscopie characterization, 522.2py. 525-27 and 530 and have

been crystallographically characterized and c o n h highly coordinated structures.

Compound 522.2~ shows bismuth in a sevm coordiaate distorted pentagonal

bipyramidal environment with the pyridinc donors in the axial positions pi-N 2.534(8)

and 2.592(9)A]. The equatoriai sites an occupied by two cir dithiolate sulfur atoms pi-S

8 8 2.545(4) and 2.592(9)A], an intermolecular sulfia contact pi-S 3.443(5)A], and two

nearly equivalently bound chlorine atoms [Bi-Cl3.111(4) and 3.23 1 (s)A], which bridge to

two separate bismuth centers and fom an alternathg Bi-CI polymeric backbone. The seven

coordinate environment of 525 (isostructural with 526) is occupied by a c h l o ~ e atom [Bi-

Cl 2.682(5)A], the two thiolate sulfvr atoms [Bi-S 2.541 (6)A], as well as a cross-ring

intramolecular donation b m the thioaher sulfur (ether oxygen for 526) [Bi4 2.849(5)A].

Iwo thiolate sulhu contacts Bi-S 3.534(*], and a long chlorine contact [Bi-Cl

3.285(6)A], nom a neighbouring molecule complete the coordination sphere. n i e tethered

bicyclic compounds 527 and 530 show similar iatramolecularly bound folded structures

with bismuth in six or seven u>ardinate cnvironments. Both compounds have similar

endocyclic Bi-S bond distances pi-S 2.~52(7)-2.599(4)A], while 530 shows slightly longer

cross-ring sulfùr contacts [Bi-S 3.07 l(5) and 3.197(4)A] than 525.

527 530

The anions [~i,(mntlJC,]~- and [B i ,bo lXJ2- 53641 are al1 speculated to be

dinuclear species, though no supporting data were obtained. The structure of the

tetraphenylarsonium salt I p h 4 A s ] p i m 2 J 543'*' shows a six coordinate bismuth center

chelated by two dithiolate ligands [Bi-S 2.664(7)-2.836(8)A]. Long sulfur contacts f~om

543

two adjacent molecules [Bi-S 3.238(10) and 3.182(10)A] create an infinite polymeric

chain.

5.3.2 Thiolatocatboxy~a~es

Table 5.3 Analytical &ta for thiolatocarboxylate compounds.

Compound yicld X m E 1 N M ( m 5 . n ) . R p A R M W

90 The few isolated examples of bismuth thiolatOcaTbOxylates have been prepated

similarly to both thiotates and carboxylates. Syntheses typically involve reaction of the

ligand with a basic bismuth salt or with the addition of base to ensure deprotonation of the

carboxylic acid group.

The infirared spectra of the tbioglycolic acid (mercaptoacetic acid, H a , 2-

mercaptopropionic (H22mna), 3-mercaptopropionic acid (Hdmna), and thiosalicylic acid

(H,tsd) complexes @i(L)(HL)] 5 4 4 4 y suggcst a polymeric structure, with bridging

mercaptocarboxylate Ligauds and four coordinate bismuth atoms.

H7&a w m W H.>3mDa H 2 W

A very complex octanuclear arrangement is observai for the ûis(thiosalicy1ate)

compound [{Bi,USaL),,~d~nf)~}(hf)~] 548;" With a C, symmetry and two unique bonding

situations for bismuth. One bismuth center (Bi') is chelated in an $0 (thiolate, carboxylate)

manner by t h e a ligands fonning six-membered -BiSCCCO- rings. The three sulfur

atoms are in afic arrangement [Bi-S 2.596(8)A] and al1 three oxygen atoms bridge to other

bismuth centers [Bi-O î.ï4(2)A]. The second unique bismuth center (Bi2) is chelated by

one ligand in an $0 manner [Bi-S 2.567(5)A; Bi-O 2.46(2)A] and two ligands in an

as-etrical 0,O ' manner [Bi-O 2.2~2)-2.79( 1)A] forming four-membered -Bioco-

rings. The oxygen atom of the S,O ligand and the more weakly bound oxygen atoms of

the 0,O '-w ligands bridge to neighbouring bismuth atoms. The coordination sphere is

completed by awoxygen atom Fi-0 2.60(2)A].

The unique trifiinctional aminothiolatocarboxyIate D-(-)-peniciilaminato-OJJV

compound [ B i w l ] 54gdM shows the Ligand chelating bismuth in a OSJI'manner

[Bi-O 2.414(5)A; Bi-S 2.527(2)A; Bi-N 2.345(6); Bi-Cl 2.680(2)A] forming botb a - BiSCCN- and a -BiOCCN- ring. Long contacts h m a chlorine atom [Bi-Cl 3.182A] and

two carbonyl oxygen atoms of neighbouring molecules [Bi-O 2.779(5) and 2.698(5)A]

create a polyrneric structure and a seva coordinate environment.

5.3.3 Hydroxy-/Alkoxy- and Ketothiobtes

Bifimctional thiolates incorporating a hydroxy- p u p have been extensively studied

and show a rich reaction chemistry. nie bis(hydrOxyethanethio1ate) compounds

[Bi(SCH,CH,OH)JJ (X = NO,^ Cl, Br) 550.52 are prepared h m the naaion of w o

92 equivalents of 2-mercaptoeulanol with the appropriate bismuth salt,' wwhile the perchlorate

sait (R = CIO4) 553,- is prepared h m a stoichiomeûic reaction in dilute perchlonc acid.

The impediment of maximum thiolation suggests some decrease in Lewis acidity of the

bismuth center. The reaction of bismuth retate with mercaptoethanol gives the alkoxy-

hydroxy complex [Bi(SCH2CH20)(SCH2CH20H}] 554.' in this case, aikoxide formation is

enforced by the basic character of the -te p u p s and may also be achieved from

Table 5.4 Analytical data for hydroxy-/alkoxy- and ketothiolates.

Compaund yield X m E s c 1 R U N M (mn R p A o o R a V M S 5.n)* 1 n m R

[ s i ( s C H 2 C ~ 0 ~ ( N 0 3 ) ( H , 0 ) , 1 41-76 r x x x x x x x x x 550'-"5 (17)

[Bi(SCH2CH20H)2Cl] 551' 73-78 x x x x - x x x x (17,181

[Bi(SCH,CH,0H)2Br] 552' 19-22 - x x x - x x - x x (17,181

pi(SCH2CH20Q(C104) 1 5S34x -(17) r x - x - x - - [si(SCH2CH20)(S~2cH20H)] 29-47 x x x x x x x - x -

5543.43s (1 920)

~i(SCH,CH20H)2(CH3COO)]5553 92(21) x x - x - x x - x x

[Bi(SCH2CH,0H),] 556'""' 33-70 X X X X - x x - (2223)

[si(&),] 557'" 69-90 X X X - x - (2425)

[BiPhCH @ 1 C W (0) Ph), 12 85-90 X - X X - X - [CH2ClJ 55tP9 (26)

[BiPhCH {SI C W (0) C~HIX)~] 85-90 X X - X - (X = Me, 559, Cl 5 6 0 ) ~ ~ ~ (26)

*Syntheses:

5.17) Bi& + 2 HSRH + Bi(SRH)J + 2 HX

5-18) Bi(SRH)& + MX' + Bi(SRH)JC + NaX

5.19) Bi& + 2 HSRH + Bi(SR)(SRH) + 3 HX

5.20) Bi(SRH),X + NaOH + Bi(SR)(SRH) + NaX + H Z 0

5.21) Bi(SR)(SRH) + HX + Bi(S-

5.22) Bi(SR)(SRH) + HSRH + Bi(SRH),

5.23) Bi(OEt), + 3 HSRH + Bi(SRH), + 3 EtOH

5.24) Bi203 + 6 HSR + 2 Bi(SR), + 3 H20

5.25) BiX, + 3 HL + NE4 + BiL, + 3 (HNEtJX

5.26) BiX, + 3 HSR + 3 NaOAc + Bi(SR), + 3 NaX + 3 HOAc

reaction of 550 in basic solution?* Recrystallization of 554 h m acetic acid reprotonates

the alkoxide and gives the acetate sait ~i (SCH2CH,0~(CH3C00)] 555.' Further, the

reaction of the hydroxythiolate-alkoxythiolate 554 with excess mercaptoethano143s also sees

reprotonation of the alkoxide and the formation of the tris(thio1ate) Pi(SCH2CH2OH),] 556.

Here, maximum thiolation is driva by the consequential fornation of the nucleophilic

thiolate group. The tris(thio1ate) bas also been prepared h m metathesis reactions between

mercaptoethanol and Bi(OEt),, and involves the favourable formation of etl~anol.'~' The

compound is stable under inert atmospheres but decomposes in air, contrasting the stability

of the bis(thio1ate) products. Compounds 551-52 may alsa be prepared by anion exchange

reactions with weakly bound nitrate p u p of 550.'

A11 bisfiydroxythiolate) structures show chelating hydrox y-/alkoxyethanethiolate

ligands, forming a bicyclic amangement of five-membcred BiSCCO- rings. The six

coordinate bismuth center of 550 contains a near planar hydroxyethanethiolate ligand

550 551 554 555

arrangement with cis sulfur atoms [ B i 4 2.639(5) and 2.655(5)& Bi-O 2.63(1)A], and a

bidentate nitrate group ( B i 9 3.01(2) and 3.17(2)A] bound above and beiow the Ligand

plane and adjacent to both hydroxy- oxygni atoms. The structure of 551 is polymeric with

bismuth in a seven coordinate environment [Bi-O 2.86(1) and 2.80(1); Bi-S 2.595(3) and

2.~58(4)A]. In this case, two /c,-chlori.ne atoms, which bridge bismuth to a second bismuth

center [Bi-Cl 2.589(3) and 3.488(4)A], and a long sulfur contact h m a third monomer [Bi-

-S 3.124(4)A] complete the coordination sphere. Compound 555 shows a monodentate

acetate oxygen atom [Bi-O 2.3~(2)A] and extensive hydrogen bonding [Bi-O 2.54(2) and

2.72(2); Bi-S 2.608(7) ami 2.577(7)A]. Preliminary structural data for 553 shows a simiiar

bis-chelating stmctwe with bndging thiolate suifur atoms [Bi* 2.61; Bi-S 2.97A~ to give

a polymeric arrangement. Compound 554 is polymeric and shows a five coordinate

bismuth atom, with the fiAh contact piovided by the aikoxide oxygen of a neighbo~g

rnolecule [Bi-O 2.982(8)A]. In this casê, the bis-chelating arrangemat [Bi-S 2.527(3) and

2.564(3)A] has one shorter and one longer oxygcn contact [Bi-O 2. M(9) vs. 2.577(9)A]

correspondllig to the alkoxy- and hydroxy- Bi-O contacts, respectively.

The ethexthiolate [Bi@&),] 557'' (Ha = 2,6irnethoxybenzenethiol) has been

characterized by elemental analysis and 'H NbfR only, although a crystalline material was

reported.

The structure of the ketothiolate [Bi(PhCH {S} C H F {O) Ph), J,[CH,ClJ 558"'

shows two unique bismuth centers chelated by thne ligands in an S,O manner, with a sulfbr

atom oecupying the axial site [avg. Bi-S 2.581(4)1j] and the remainllig atoms oecupying the

basal sites of the pentagonal pyramidal arrangement [Bi-S 2.627(5)-2.73 l(3); Bi-O

2.536(9)-2.650(9)A]. Long Bi-S' contacts [Bi-S 3.494(5) and 3.551(5)A] to the empty

apical sites between neighbouring molecules creates a dimeric stnichuc and a seven

coordinate bismuth center.

5.3.4 Amino-, Imino- and Aza-Thiolates

As discussed in Chapter 2.5, bismutho complexes of thioscmicarbazone

derivatives have been prepad as antimicmbid agents. Synthetic procedutes for these

compounds are general (reactions 5.27 and 5.29) and, due to the large number of complexes

isolated, oniy sûucturajly characterized exampies are discussed here.

96 Table 5.5 Analytical data for amino-, imino- and azathiolate compounds.

Compound yield X m E s c 1 R U N M p (rxn R p A o o R a V M S o

[S~(&R,R~(H&R,RJC~~]~~ SS(29 ) x x x - x x x x x - 569 (R, = C4H3S, R2 = C&)

[Bi(tscRlRJ2(N03)] 57VM 71(27) x x x - x x - x x x -

* Syntheses:

5.26) Bi(N03), + 3 RSH + n HCI + (3+n) KOH + Bi(SR), + 3 KNO,

+4H,O + n KCl

5.27) B i o , ) , + n RSH + Bi(SR)m(N03), + n HNO,

5.28) BiCl, + 2 NaSR + Bi(SRs1 + 2 NaCl

5.29) BiCl, + RSH + Bi(SR)C12 + HCl

5.30) BiCI, + HSRSH + NaN, + [Bi(SRS)N,] + 2HC1 + NaCl

The earliest aminothiolate bismuth compounds prepared were of

2-amuiobenzeaethiol (Hêbt)..YY4 The c o m p o d Bi- 561U) and the protonated

ammonium analogue Bi(H&),C13 562 are prepared similarly, with the d t i n g product

determineci by the tinal reaction p H . 561 is poorly soluble in organic solvents and

w4u appears to be air and moishm stable for a p e r d of weeks. The üis(thio1ate) compound

[si(2-SC,H,N-S-SiMe&] 564 is unstable to weak electrophiles (e.g. MC1 ), giving the

bismuth halide and the ~ u l f i d e . ~

For Bi(&& 561, participation of the amino- group in the binding of bisnuth is not

suggested by solid state IR, negating the presence of a chelating structure, while solution IR

spectra also suggests the presence of an uncoordinated NI& group. nie £ k t structurally

charac tenzed amino-thiolate [Bi(SCH,CH2NH~(N03~20)] 563"' shows a similar

bicyclic structure to the hydroxy-/alkoxythiolatts 550151 and 5-55, but with five-

membered -BiSCCN- rings [Bi-S 2.549(2) and ~.589(2)A]. Cooidination to the bismuth

center by a monodentate nitrate group and a water molecult gives a fomal coordination

number of six, while intemolecular contacts b m neighbouring sulfur atoms [Bi-S

3.5 1 7(2) and 3.550(2)A ] mate au eight co-ordinate distorted odahedral nivironment for

bismuth and a one-dimensional polymeric structure. The short bismuth-nitrogen [Bi-N

2.462(5) and 2.455(6)A] and long bismuth-oxygm [Bi-0,3.004(6)A; Bi-O,

3.107(6)A ] bond distances suggest an i n d stability for the bicyclic unit and decreased

Lewis acidity of the bismuth center.

Related to these aminothiolate complexes are those conbining ligands which

incorporate a nitrogen donor into an aromaîic ring. The tris(thio1ate) compound [Bi(2-

SC,H,N-3-SM%),] 564& has a distortcd pentagonal pyramidal geometry around bismuth

incorporating a pyramidal Bis, arrangement [Bi-S 2.544(6)-2.647(7); Bi-N 2.69(2)-

~.83(2)A]. The inverse relationship of the B i 4 and Bi-N bond distances suggests a greater

ring strain for the resulting four membered -BiSCN- rings than the -BiSCCN- rings of 563.

Bis(2-phenyl-8-mercaptoquinolinato) @me) bismuth chloride pi@&2C1] 56SU7

shows bismuth in a five coordinate distorted square pyramidal environment. The axial and

basal sulfùr atorns [Bi-S 2.532(3) and 2.591(3)A respectively] and the chlorine atom pi-CI

2.579(3)A] are in a fac arrangement, The long bismuth-nitmgen distances [Bi-N 2.628(9)

and 2.880(7)A] may be a consequeme of ring wPin enforced by the sp2 carbon backbone

atoms of the -BiSCCN- ~ g s , while the formation of the bis(thio1ate) is a possible

consequence of the induced decrease in Lewis acidity of the bismuth center by the imino

nitrogen donor, as well as the steric bulk of the ligand. A long sulfùr contact to the mpty

R = Me, ii-q = Ph, Hpmq

apical site [Bi-S 3.304(3)A] dimerizes the compound and increases the coordination

number of bismuth to six. The mlaîed trîs(methyi-) d o g u e [Bi(mmg),] shows

bismuth chelated by three 2-methyl-8-mercaptoquinoünate Ligands [Bi-S 2.571(2)-2.623(3);

Bi-N 2.689(4)-2.796(4)A] in afac arrangement with no intmolecular contacts, giving a

sixcoordinaîe distorted octahedral geometry for bismuth. A similar structure is observed

for the 3-mercapto- 1 ,Sdiphenylfomazan (dithizone) wmpound Bi(HPh), 56fu9 [Bi-

S 2.607(3)-2.6 13(3)A; Bi-N 2.678(8)-2.746(1 o)A], forming five membered -BiSCNN-

rings.

Examples of mono-, bis- and tris- complexes of various thiosemicarbazone

derivatives (H&çR,Ra have been prepared." The b i s 0 complexes [Bi(&R,R32(N0,)]

568 and ~ i ~ R I R ~ ( H & R I R ~ C I J 569 (RI = C,H,S, R, = C&3 bath show the & iigand

100 chelating in an Sa-manner, while in 569 [Bi-S, 2.527(3); Bi-N 2.5 1 S(8); Bi-CI 2.605(4)

and 2.630(4)A] one of the ligands bonds the bismuth =ter in a monohtate fashion as the

thione tautorner Bi-S, 2.992(3)A]. Compound 568 shows a similar bond arrangement to

568 569

the arninothiolate 563, with the a h c e of a bonded wata molecule [Bi-S 2.56 l(3) and

2.565(4); Bi-N 2.438(10) and 2.445(11); Bi-O 2.889(1 l)A]. The (RI = C,H,N, R, =

NCJ3,J derivatives [Bi&RlRJ2(N0,)J 570 and [Bi&R,R$lJ 571 both show the

Ligand chelating in a tridentate S,N,Wmanncr, forming -BiSCNN- and BSICCN- rings.

Compound 570 shows a monodentate nitrate anion and a seven coordinate environment for

bismuth [Bi-S 2.584(4) and 2.654(4); Bi-N, 2.471(8) and 2.581(8); Bi-N, 2.71 l(10) and

2.649(9); Bi-O 2.73 l(11 )A]. nie mono&& cornplex 571 dimcrizes via bndging chlorine

atoms, giving a total coordination number of six for bismuth pi-S 2.583(3); Bi-N,

2.355(8); Bi-N, 2.501(8); Bi-CI 2.585(3); Bi-Cl 2.791(3)A].

The 2,6-diacetylpyidine bis(thioJemicarbaz0ne) W2dabts) compound piCdants]N,]

572." shows bismuth in a six coordinate distortcd pentagonal pyramidal environment. Ail

572

basal sites are occupied by the SJV,N'JV",S'-pentadentate ligand [Bi-S 2.685(7) and

2.717(8); Bi-N, 2.46(2) and 2.58(2); Bi-N, 2.44(2)A~ with an azide nitrogen in the

apical site [Bi-N 2.25(2)AJ.

5.4 Thio- and DithiocarbosyIates

Bismuth thio- and dithiocarboxylates (Figure 1.1) are interesthg species in that they

may provide a usefiil link between thiolate chcmistry and carboxylate chernisby. The

thiophilicity of bismuth allows for the fomation of hydrolyticaily stable complexes, while

the group chelates and bridges bismuth in an d o g o u s manner to the carboxylate

functionality. While dithiocarboxylates have been extemively studied, t h m have been few

102 studies into thiocarboxylates of bismuth. The incorporation of both a hard oxygen atom and

a sofi sulfur atom or two sulhir atom gives way to structural divmity and allows for the

group to bond as a bihctionai ligand. As a result, examples of mono-, bis-, tris and

tetra(dithiocarboxy1ate) species, as well as mixed ligand complexes, have been prepared.

Characterization data for these compounds are included in Tables 5.65.7.

Table 5.6 Analytical data for thiocarboxylate compounds.

Compound yield X m E s I N (nai Sa)* R p A o R M

"Svntheses:

5.31) Bi@, + 6 RCOSH + 2 Bi(SOCR), + 3 H20

5.32) Bi(OOCCH,), + 3 RCOSH -B Bi(SOCR), + 3 CH3COOH

5.33) Bi(SPh), + 3 RCOSH + Bi(S0CRl3 + 3 PhSH

The series of tris(thiobenu,atcs) of the g a i d formula [Bi(SOCC$14R), ] 573-

75452.453 are themally stable, with 574 being much more soluble in orgaaic solvents than the

other derivatives. In 574, al1 three thiocarboxylate ligands chelaie to form four-mernbered -

BiSCO- rings pi -S 2.630(3)A], with quite long bismuth*xygen bond distances pi -O

1 O3 2.752(6)A] and the three sulfra atoms in a pyramidal /ac anangement. Long contacts from

the three sulfur atoms of a neighboring molecuie mi-S 3.498A] increases the coordination

number of bismuth to nine.

5.4.2 D W iocarboxyIates (Dithiocarbamates, Dithioxanthates)

The majority of dithiocarboxylate compounds that have been prepared are

dithiocarbamates 0, while thm are also several examples of dithioxanthates (Rdtx).

Both classes of compolmds exhibit a variety of organic R groups. &ed dithiocarbamate

compounds 51 10-117 include combinations of the following R (R') groups: Et, CH2Ph,

C,H,, C,H,, and C,H,-

104 Table 5.7 Analytical data for dithioçuboxylate compounds.

Compound yield X m E s c 1 U N M T C M (m5.n)* R p A O O R V M S G V W

IO5 Table 5.7 Analyticai &ta for dithiocarboxylate compounds (continuai).

Compound yield X m E s c I U N M T C M (m5.n)* R p A O O R V M S G V W

1 n R A [Bi(Et&), 1 5 1 0 3 ~ ' ~ ~ -(44) x x - x x x x x

[si(Tr&),] 51 û447u7""n -(u) ~ X - X - X - - - -

CsiOim31@ = c-call -(44) x - - - x - - - - - - 51 os, CHPh 5106)~'-.~"

[Si(EtrnA -(37,45) - - x - - x x - - - - x (X = Cl 5107, Br 5108)*'

[NEt,] [Bi(Etm4] 51 09*74*m - (46) x - x - x - - - - - -

IBi(&&&(R'2dlç)I 58-90 X X X - X X X X - x 5110-1 lys9 (47,443)

[Bi(Etdtx)2(Meg-Ù] 51 1- -(4Q x - - x x - - - -

[s i(R,dt~)~(Ettdgc) 58-97(48) - x x x - x x x x - - x (R =Et 5119; {CH,), 5120)

[si(Et&&Et&&J 5121" -(48) x - x x - - - -

[Bi(eac&J 5122&' gg,go x - - - - - - - - - - - (49,501

5vntheses:

5.34) BiC1, + 3 CS, + 3 NHR, + B i ( S 2 W 3 + 3 HCl

5.35) BiONO, + 3 HS,CR + (n+l) NH, + n HCI + Bi(S,CR), + H,O

+ NH4N03 + n NH,CI

5.36) BiC13 + 3 NH,(S2CR) + Bi(S,CR), + 3 NH,CI

5.37) Bi(S2CR), + X, + Bi(S2CQX + by-pT0duct.s

5.38) m Bi& + n Bi(S2CR), -+ (m+n) Bi(S,CR)),,&

5.39) BEI3 + 2 NH,(S2CR) + L + [Bi(S,cR)$I(L)] + 2 NKCI

5.40) Bi(S,C& + BF, + Bi(S2CR)z(BFJ + by-prducts

5.41) Bi(S2CR)X2 + L + [Bi&CR)J&)I + by-pducts

5.42) Bi(S2CR)12 + lrJEt4]X + (NEt4J[Bi(S2CR.)IA

* S vntheses: (continueci)

5.43) Bi(S2CR)Br2 + L + [HL]Pi@,CR),Br,,,J + by-pralucts

5.44) BiC13 + 3 Na(S,CR) 4 Bi(S2CR), + 3 NaCl

5.45) 2 Bi(S2CR), + C a , + 2 Bi(S2CR)J + Cu(S,ClQ

5.46) Bi(S,CR), + Nws2w + rNEt,llBi(S2CR)Il

5.47) Bi(S,CNR321 + CS2 + 2 + [Bi(S2CNRh(S2CNR'J

+ NHS2I

5.48) Bi(S2CR),X + M(S,CR') -, Pi(S,CRh(S,CR')I + MX

5.49) BiCI, + 3 HS,CR -P Bi(S,CR), + 3 HCl

5.50) BiOCl + 3 HS,CR + Bi(S,CR), + H 2 0 + HCl

Several methods have been uscd to prepare mono-, bis-, tris- and tetra- examples

of dithiocarbox y lates. These complexes exhibit varying degrees of solubility and

stability toward hydrolysis, oxidation and thexmolysis. The dithiocarbarnate [Bi(Et&&]

57645U56 is soluble in chloroform, carbon disulfide and carbon tetrachlonde, monorneric

in solution, and fairly air stable. The bis(dithiocarbamate) tetrafluoroborate salts

[Bi(R&),(BF,)] 590-92''' react with water, while the bis(dithioxanthate) halides

pi(Et&q (X = Cl 5107, Br 5108)'% are thennally stable but susceptible to hydrolysis.

Mixed-ligand complexes have also bcen synthesizeû, which incorporate two differnt

dithiocarbarnate or xanthate ligands, or both a dithiocarbamate and a dithioxanthate ligand.

These include mixed dithiocarbamate complexes [Bi(R&&(R'&) 1 51 1 ~ 1 1 7,'s9 a mixed

dithioxanthate complex pi(Et&&(Mc&Q] 51 18,- and mixed dithiocarbamate-

dithioxanthate complexes [ B i o @ u ] 51 l9 -12F and pi(Et&@t&.&J 51 21 .-

Compounds 51 l & l l 7 and 511P120 arc air and solution stable, while the mixed ligand

complexes 51 19-120 are more stable than tris(O-ethyldithioxanthate). An analogue of the

1 O7 2-ethylamino derivative complex [Bi(eac&] 5122&' involving the unsubstituted ligand is

reported without a formula designaion or characterization &ta.

There are several examples of tris(dithiocarbamate) compounds, al1 of which

contain three asymmehically S,S'-chelated ligands, forming four-membered -BiSCS-

rings. In each case, the shorter Bi-S contacts are in a fac arrangement, and varying

degrees of intermolecular Bi-S bonding create dimeric structures. The s t n r c t ~ r e ~ ~ ~ of

the diethyl analogue [Bi(&&&] 576'- [BiS2.595(5)-2.964<4)A] shows bismuth in a

seven coordinate environment, with a single long sulfur contact f?om a neighbouring

moiecuie p i - S 3.210(4)A~. The structure of the dieîhanol analogue

[Bi({HOCH,CH,)&), ] 5 7 y shows bismuth in an eight coordinate distorted square

antipnsm bonding environment [Bi-S 2.669(7)-2.885(7)A]. In this case, dimerization is

through four bridging sulfur atoms of two ligands [Bi-S 3.076(9)-3.179(9)A]. The

pyrrolidhe analogue Pi((CH,}&,] 5 7 p shows two unique bismuth atoms in both six

and seven coordinate mvironments [Bi-S 2.6 12(7)-3 .O l7(8)A 1. Here, only one of the

1 O8 bismuth centers receives a long Bi-S contact nom a ncighbouring molecule [Bi-S

A nurnber of bis(dithiocarbamate) halide wmplexes have also bem prepared and

conductance measurements of the bromo analogues [Bi(R&&Br] 579-83.66 suggest that

these compounds are non-electrolytes in nitrobenzene, while molecular weight

measurements of both the bromide and iodide analogues (Bi(R&,u 5 8 4 8 e 7 suggests

that they are b e r s in solution. Spectroscopic data for the iodo complexes suggest that

the dithiocarbarnate ligands function as bidentate ligands.

The bismuth centers of 579,584Im and 589- are each coordinated to two

asymrnetrically bound SJ'-dithiocarbamate ligands. Intemolecular halide and sulfur

contacts again ailow for varying degrces of polymerization. Compound 579 (NEC

omitted from drawing) shows tetramer-based polymeric network with two unique

bismuth environments. One bismuth center (Bi1) [Bi* 2.6~7(4)-2.843(7)A] coordinat es

two cis bndging fi- and fi-bromine atoms [Bi-S 3.066(2) and 3 . ~ 2 ) A . fe~pectively],

while a second bismuth center (Bi2) [Bi-S 2.641(5)-2.814(5)A] is cwrdinated to three fac

bridging h- and A-bromine atoms b: Bi-S 3.104(2); f i : Bi-S 3.232(2) and 3.390(3)A].

109 The structure of 584- shows a one-dimensional polymeric structure with a -Bi-1-Bi-1-

backbone, facilitateci by two cis bndging A-iodine atoms mi-1 3.257(2) and 3.3~4(1)A],

and bismuth in a six coordinate environment [Bi-S 2.646(4)-2.860(5)A]. The

bis(dithi0carbamate) thiourea adduct [Bi({CH2)&&C1(&)J 589."' shows bismuth in a

seven coordinate environment Pi-S* 2.624(4)-2.805(3)A; Bi-S,, 3 .O 1 7(4)A 1. A

dimenc structure is fomed through two cis p&lorine atoms [Bi-Cl 2.9 1 l(4) and

3.187(4)A].

Conductivity data for the tetrafluoroborate saits [Bi(R&&(BF,)] 590-92'''

suggest that the compounds are univalent-electrolytes in nitrobmzme, while molecular

weight measurements in dichloromethane suggests the compounds are monomerïc in

solution.

Examples of mono(dithiothiocarbamate) dihalides have also been prepared. The

ethyl denvatives [Bi(Et&)X,] 593m*4a'-954m a2are isostructural and show a one-

dimensional polymer with bismuth in a seven coordinate envir~ment.'~' The

110 coordination spheres are occupied by an S,Sdithiocarbamate ligand pi-S 2.594(3)-

2.690(5)A], two pairs of cis &-halogen atoms which bridge to two neighbouring bismuth

centea [Bi-X: Cl 2.673(3)-3.165(3); Br 2.820(2)-3.305(2); 1 3.032(2) and 3.~01(2)A],

and a bndging sulhrr atom fiom a neighboring molenile pi-S 3.378(3)-3.462(5)A].

The intermediate mono-/bis- complexes of empirical formula

[Bi,(Et&&X,(dmn] 596-98"' are also isostructural aad show a pentanuclear unit with

two six and one seven coordinate unique bismuth cnvironments. One bismuth atom (Bi')

is coordinated by two SJLdithiocarbamate Ligands Bi-S 2.6q 1 )-2.8 1 (1 )A], a terminal

halogen atom pi-X: Cl 2.89(1); Br 3.050(2); 1 3.278(3)A~, a bndging fi-halogen atom

[Bi-X: Cl 3.42(1); Br 3.5 15(3); 1 3.706(4)A], and a bridging ,u3-halogen atorn pi -X: Cl

3.43(1); Br 3.533(3); 1 3.680(3)A]. A second bismuth center (Bi2) is in a similar bonding

environment pi-S 2.61(1)- 2.8ql)A; Bi*-X): Cl 3.04(1); Br 3.194(3); 1 3.42 1 (4)A; Bi-

@,-X): CI 3.42(1); Br 3.469(3); 1 3.582(3)A], but with the absence of the temiinal

halogen atom. A third bismuth center (Bi3) is coordinated to bndging &-halogen atoms

[Bi-X: Cl 2.68(1) and 2.74(1); Br 2.860(3) and 2.862(3); 1 3.07q3) and 3.053(3)A] and

p3-haiogen atoms pi-X: Cl 2.71(1); Br 2.855(2); 1 3.079(3)A] only.

Several anionic complexes have also bccn prcparcd, including the monoanionic

compiex ~ t , J ~ i ( E t g f ç ) 1 3 ] 599 and the partially brominated [NEt,][Bi(Et&&Br]

11 1 5100:n and the dianion [HPY],[Bi,(Et&&Br,,] 5101 ."' The dimeric anions of 599 and

5100 are isosûuctural and show bismuth in a six coordinate distorted octahedral

environment. In addition to the S,S'-dithiocarbamate ligand [Bi-S 2.649(5)-2.770(6)A],

the bismuth coordination sphere is occupied by axial and equatoriai terminal halogen

599-51 00 5101

atoms [599: Bi-1 2.965(1) and 3.091(1); 5100: Bi-Br 2.813(2)A and Bi-1 3.006(2)A] and

axial and equatorial bridging iodine atoms pi-1 599: 3.190(1), 3.29 l(1); 5100: 3.1 15(2),

3.244(2)A]. The anion of 5101 shows a tetranuclear unit with bismuth in a six coordinate

environment. The coordination sphere contains one tenninal [avg. Bi-Br 2.94(1)A] and

three bridging bromine atoms [Bi-Br 3.24( 1 )-3 .34(l )A], and an S,S'-dithiocarbamate

ligand [Bi-S 2.68(3)-2.73(3)A]. Therc is aiso one very long contact to the empty site on

each bismuth center [avg. Bi-Br 3.74( 1 )A].

A number of dithioxanthates have Ptso been prepared, Uicluding the tris- products

[Bi(R-),] 5102-106,"~'~ and have structures similar to the tris(dithiocarbarnate)

analogues. Conductivity measurerncnts suggest that the ethyl derivative pi(Eth-L),J 5103

dissociates in ethanol solution The structure of [B~(MC&)~] 5102'~ pi-S 2.5%(3)-

2.998(4)A] shows a dimeric unit anaiogous to [Bi(Et&&] 576, where the mcipmcation of

a long ~ i - s contact pi-S 3.405(1)A] h m a ncighbouriag molede creates a dimeric

arrangement. The c yclohexyl- and knzyl- analogues 51 05 [Bi-S 2.599(2)-3 .O63(2); B i 4

112 3.21qî)A] and 5106 [Bi-S 2.597(1>3.025(1); B i 4 3.375(1)A] have analogous

stru~tures.~~ The one-dimensional polymeric anangement of ~ 1 0 3 ~ ~ [Bi-S 2.605(8)-

2.99(1 )A] involves two long suifur contacts h m two neighbouring molecules Bi-S

3.3 52(8)-3.627(9)A], giving a bismuth-dfk "1addei'-type pol ymeric backbone. The

5103 5104

structure of pi(?%,&&,] 5104475*478 is similar to that of 5102, but in this case the long

bismuth sulfur contacts of the molecular unit are to two separate neighbouring molecuIes,

fonning a one-dimensional coordination polper [Bi4 2.682(2)-3.175(2); Bi--S

2.842(2)A].

Spectmscopic data of the bis(dithi0xanthate) haiides [Bi@- (X = Cl 5107, Br

51 08)"~ suggests solid state polyrneric structures, while molecuiar weight measurements

suggest that they are monomeric in solution.

The monomeric anion of the teîzakis(dithioxanthate) w, J [Bi(Etm4] 51 0g4"

shows an eight coordinate bismuth center bound by three asymmetrically bound [Bi-S

2.803(11)-2.972(10)A] and one syrnmetrically bound pi-S 2.833(6) and 2.859(9)A] S,S-

113 dithioxanthate ligand?

Although there are no examples of stnicturaîly characterized dithioczubarnate and

dthioxanthate rnixed ligand complexes, infraied data for (Bi(R#tc),(EtpqO] 51 19-1 2 0 ~ ' ~ and

[Bi(Et&)(Et&&J 5121- suggest that dithiocarbamate ligands are more strongly bound

than dithioxanthate ligands due to 2-SS,C=W resonance.

in addition to the dithiocarbamate and dithioxanthates, 2-aminocyclopent-1 -ene- 1 -

dithiocarboxylic acid (Ha derivatives have ken cmployed as iigands for bismuth. The

2-ethylamino derivative complex Pi(eacd)J 5122*' shows a six coordinate distorted

R = H , H a R = Et, Hgacd

trigonal antiprismatic environment for bismuth, with three asymmetrically bound S , S

dithiocarboxylate ligands [Bi-S 2.617(2 )-3.108(2)A]. A long bismuth Julfur contact [Bi-S

3.689A] creata a weakly bound dimaic structure similar to 576.

5.5 Summary and Conclusions

In surnmaq, the data for bismuth-thiolate compounds presented in this chapter

(see Figure 5.1) is intended as an introduction to the synthetic and structural chemistry of

bismuth thiolates and as a platform for discussions regarding bifunctional thiolate

chemistry in Chapters 6 and 7. For the most part, the database for the thiolate chemistry

of bismuth is extensive, but is composed of examples which represent unique complexes

114 for a particular Ligand, rather than M e s of rclatcd compounds establishing fiuidamental

synthetic guideluies and illustrating g e n d chernical properties. For monothiolate ligand

complexes, the high thiophilicity of bismuth routinely imposes multithiolation and results

in tris- thiolation in mort cases. The introduction of an electmn-withdrawing fluorinated R

group increases the Lewis acidity of the bismuth centter and facilitates the isolation of

S"E \ C E-Bi-S

/ / \ \ R-S E-R

Figure 5.1 Bonding situations observeâ for bismuth thiolate complexes.

pentathiolate dianion and a series of Lewis base adducts, al1 of which exhibit octahedral-

based geometries. The thiophilicity of bismuth is huther demonstrated by the foxmation

of highly coordinated and stable monocyclic bis(thio1ate) and "tethered" üis(thio1ate)

complexes from dithiolate ligands. Few bismuth thiolatocarboxylate complexes have

been prepared and show the ligand chelaîing bismuth in both $0 and 0,0 capacities,

result ing in extensive intermolecular bonding typical of the carboxylate huictionality .

Although there are tris(thiolate) examples of complexes incorporating bihctional

115 ketone-, imino- and azathiolate Ligands, the introduction of secondary electrondonating

fùnctionalities ailows for a potential dccrta~e in Lewis acidity for bismuth and control of

thiolation. This is demonstrated by the preference for a bicydic bigthiolate) arrangement

of bismuth hydroxy- and amino-ethanethiolates, as well as the isolation of bis- and

rnonothiolate complexes of the thiosemicarbamne ligand. Mono- and dithiocarboxylates

chelate and intermolecularly bond with bismuth analogously to the carboxylate

firnctionality, and may be viewed as bifhctional thiolatts, incorporating a secondary

ketone or thione donor. Oaly triS(monothiocarboxylate) complexes have been reported,

while dithiocarboxylates cmently represent the most varied coordination number for

bismuth with examples of mono-, bis-, tris- and tetra- complexes known, but involve a

range of ligands and a variety of synthetic procedures.

116 Chapter 6. DeCining and ControUg the Aminatbanethiolate Cbemistry of

Bismuth(III): Synthesb and Comprchcnsive Cbaracterization of Homologous

Thiolatobismuth Series

6.1 Introduction

Difficulties associated with isolation and characterisation of bismuth compounds

have precluded comprehensive assasment of their relative stability. Isolation yields are

oAen not reported or are low, and are rarely evaluated in t m of other possible reaction

products. Nevertheless, the synthuis and chemisûy of these compounds remains

superficially understood in that most compounds have been isolateci under specific

conditions and without investigation of other possible reaction products. Moreover, there

are few exarnple~~"~ of studies hto the repmducible interchange between derivatives or

related compounds, and variation in antimicrobial bioa~tivity'""'~ among the members of

systematic senes of structurally simple compoundsU suggests a stnicture/activity

relationship for the bismuth envkonment.' Such realizations highiight the need for

universally applicable synthetic procedures which enable control of the coordination

chemistry for heavy elements. Comprehensivt structural and spectroscopie

characterisation of systematic series of compounds represents the most reliable

fundamental foundation for rational chernical development.

The potential utility of chelating bifunctional ligands, containhg one thiolate

moiety and an auxiliary donor to mediate the thiophilicity of bismuth is demonstrated by

isolation of the bicyclic bis~ydroxyethanethi01ato)bismuth complexes 55041,553 and

5553,4~~,436 as most readily isolatcd products.'" Further, the andogous

117

bis(aminoethanethio1ato) bismuth nitrate compla 563 [hereafter denoted ~(N03).H,0]

is the oniy reported product of the reaction between Bi(NO,), and aminoethanethi01 in

acetic acid."' The penicillarnine compound 549 represents a unique example of a

mono(thiolate), but is facilitated through the introduction of an anionic carboxylate

fun~tionality.'~

in addition to the examples presented in Chapter 5 (561-63), there are rare examples

of spaîmscopicaily characterized oqpobismuth aminobenzenethiolate @J& complexes.

The preparation of both the mono- and bis(thio1ate) compounds [BiPh,(&)lU7 and

piPh(abtt)JW3 h m Hg& and BiPh, represent the only reports of variable thiolation h m

common starting materials. However, it is odd that the formation of the monothiolate

product involves a greater stoichiometry of thiol reactant [l : 1 vs. excess BiPh, for the

bis(thio1ate)J and heating, both conditions which would be expected to promote maximum

metathesis. The methyl bis(thio1ate) analogue [ ~ i ~ e ( â b t M F and a series of dimethyl

thiolate compounds Me$3iSRa were R is a nitrogen substituteû organic ring, are prepared

fiom metathesis reactions involving allrali metal thiolates and organobismuth haiides.

To exploit the realization of variable and minimal thiolate coordination, a

comprehensive assessrnent of the reactions involving BiCl, or Bi(NO,), with

arninoethanethiol or dimethylaminoethanethiol was perfomed at various stoichiometries,

in the presence of KOH. Addition of base serves to activate the thiol (to a thiolate), and

thereby provides a reliable and direct control of the extcnt of metathesis. in this manner,

this chapter defines the conditions to preparc and characterize homologous series of tris-

0, bis- and rnono(anilnoethanethiolato)bi~~~luth complexes = and d~). and

the solid state structure of at least one example of each has been confhed, thereby

118 clarifying and expanding the lixnited p r e h b a q conclusions arising h m previous

spectroscopie 4 ~ . 1 « ) . ~ I.w,us.~w.~~ I and structural studies.'"*us

6.2 Results and Discussion

The aminoethanethiolate and dimethylaminoethanethiolate anions react rapidly

with BiC!, or Bi(NO,), to give yellow solutions h m which crystalline materials have

been isolated by various solution concentrathg procedures. Isolates fiom reactions of the

dimethylaminoethanethiolate anion with BiCl, reflect the respective reaction

stoichiometry [3 : 1 gives Ume), 2: 1 gives m(Me), 1 : 1 gives m e ) ! . In contrast, tris-

thiolation to give a can only be achieved with the parent aminoethanethiolate ligand by

introducing a heavy excess (5: 1) of the anionic ligand, and the precise 3: 1 stoichiometry

affords =Cl.

R = H for compounds labeled @!! R = Me for compounds labeled Uwe)

The apparent impedance of complete metathesis for the parent ligand is likely due to

coordinative interactions nom the pendant amina, which inevitably mediate the Lewis

119 acidity of the bismuth center. The apparent weaker donor ability of the dimethylamino-

functionality @& of NMG 4.13) over that of the amino- group (pK, of NH2Me 3.35) is

counterintuitive and is accredited to the relative increase in steric restrictions, as observed

in the methylated (amine) derivative m(Me)CI]. Also, the excess Ligand is anomalously

soluble in the reaction mixture to give and mC1 shows an enhanced solubility in the

presence of excess ligand. This may be interpreted as indications of the incipient

formation of anionic poly-thiolates of the type [Bi(SCH2CH,NRJ, 1- and

[BiX(SCH,CH2NR&]', respectively, the lability of which may be reqmnsible for the

broad signals observed in NMR spectra (vide infra), and the existence of which

contributes to the incompleteness of thiolation.

Reactions involving Bi(N03), with the methylated ligand typically give oils on

evaporation of solvent, so that m(Me)NO, and &(Me)N03 have not been isolated, and

an insignificant yield of a ( M e ) (identified by Raman spectroscopy) was obtained from a

3: 1 reaction stoichiometry. Further, the lability of the nitrate co~ntenon'~ suggests that

the monothiolate compound 6ç(Me)N03 is not likely to be isolated. Nevertheless, the

parent compound m N 0 , is d l y obtained both as the previously reported hydratai

f ~ r m , ~ ' and as an unsolvated solid. The forma is isolated h m relatively dilute solutions

containing excess ligand (3: 1 stoichiomehy), by slow crystal growth over a number of

days. Rapid crystal growth h m preconcnitrated solutions of appropriate stoichiometry

give @NO3. Thee synthetic routes may be viewed as improvements over the iiterature

preparation,us which could not be repeated despite several attempts and of which the

original reaction conditions an questionable. The naftion involves similar reactants but

is performed in acidic media, and would be expccted to give ammonium salts.

120 Reactions of BiX, with dimethylaminoethauethiol or dimethyIaminoethanethio1

hydrohalide give m(Me)X (X = CI, Br) as an essentially quantitative precipitate,

independent of stoichi~rnetry.'~~ This dramatic thermodynamic preference for

coordination of the ammoniwnethanethiolate tautomer of the thiol is confirmed by the

high yield substitution of nitrate for chloride/ bromide observed in the 3: 1 reaction of

HSCH,CH,NMepHX with Bi(NO,),. Moreover, precipitate mixtures containing

6CWe)CI and KCl produce m(Me)Cl when washed with water, illustrating the labile - and basic nature of the amine chelate interaction.

Except in the case of de(Me)X [obtained as a analytically pure powder in 97 (Cl)

and >95% (Br) yield], the isolated yields do not generally illustrate quantitative reactions,

that are sometimes observeci for thiolate-bismuth systems,' and each reaction mixture

may contain al1 of the metathetical products that have been iso1ated over the range of

stoichiometric conditions. Nevertheless, it is clear that the imposeci stoichiometries

conveniently and sufficiently enhance formation of one complex over the others to allow

for isolation by crystal growth. Compound dç(Me).'/rHCl is reproducibly obtained

(each sample characterized by X-ray crystdlographic analysis) as Pasteur isolated

crystals from a powder mixture.

Bismuth thiolates typicaily exhibit low solubilities in most solvents and strong

donor solvents are required to enable any appreciable solvation, usually with the

formation of a resilient solvent coordination compIex (tg. S22m2~y, 5 3 2 . 2 ~ and

533 ."21"32 Complexes involving the bifûnctional chelate ligands

aminoethanthiolate and hydroxyethanethiolate have substantiaily higher mlubility,

121 perhaps due to the presmce of the awiiiary donor site on the ligand, which mimics the

role of the donor solvent and occupits possible intermolecular coordination sites. As a

result, these complexes an more routinely tecrystallised and are amenable to solution

NMR spectroscopie characterization. 'H and "C NMR spectra are consistent with the

compounds retaining theu topological solid state structures in solution, but signals are

generally broad, implicating exchange processcs, possibly due to the formation of

hypervalmt anionic complexes and consequential ligand lability.

As is typical for thiolatobismuth compounds, these complexes are thennaily

sensitive and, except for compound fi and W e ) , al1 decompose (dramatic color

change) before melting. Each compound exhibits a number of usehl features in the IR

spectra, but the Raman spectra show very distinctive and intense bands below 400 cm-',

which can be conveniently used as a reliable "thgerprint" identification of crystalline or

powder matenals.

While electron impact mass spectra of thiobismuth compounds are generally

uninformative as a result of their t h e d instability, the APCI technique3 provides

characteristic fragments, the most prominent of which are the bis-thiolates and

6B(Me)' ( m h 361.41 7), and atomic bismuth (rnh 209). Other fragments include the - bismutheniurn monocycle @i(SC@.NH)]' (m/z 284), ~ i ( S ~ H , N H ~ C I J t (m/z 320) and

[Bi(SGH,NH&l+ (PmD3* (mh 393) for wl and [Bi(SC,H4NMi)Cl)+ (m/z 348) for

6B(Me)CI. A protonated molecular ion is also readily obscrved for m(Me)CI (m/z 453) - and m e ) (m/z 384). In addition to otha fiagrnents also observed for U m e ) and

6B(Me), spectra of both compounds show a solvent adduct peak [Bi(SC2H,NMwl + -

122 (dm fi]' (mk 42 1). interestingly, m(Me)Cl displays the m/z 4 1 7 ihgment, suggesting

that ligand lability allows for rearrangement to a bicyclic configuration.

The solid state structures of compounds 6& W e ) , m,, aNo30H20, =Cl,

6B(Me)CI, s(Me)*'/rHCl and m(Me)Cl have been confinned by X-ray crystallography -

(Table 6. l), although the crystal structure of dq(Me) involves positional disorder which

precludes detailed structural disc~ssion.~ As representatives of each type of complex,

crystal structure views of compounds a =Cl, rm(Me)CI, dç(Me)*L/iHCl and

6D(Me)Cl are shown in Figures 6.1-6.5, respectively (H atoms are ornitteci for clarity). -

The chelate motif of the ligand is evident in al1 structures except for that of a(Me)CI, in

which the pendant amine is protonated rather than coordinated to the Lewis acidic

bismuth centre. As O bsnvcd for the di thiolate2 and hydroxytholate3 heterocycles,

polymeric packing arrays are made possible by intermolecular Bi--Cl and/or Bi-S

interactions,'" which are distinctively long. E r n e ) adopts a 4: 1 hydrochlonde cluster

array (Figure 6.4) in which the unique chlonde anion acquires a tetragonal site, engaging

four bismuth centers and representing the third Bi-Cl (Bi-Cl) interaction for each

rnolecule of =(Me).

Bis(thio1ate) complexes involving the parent ligand, mNO3 and =Cl, are best

interpreted as ionic matenals composed of the cation da'. on the basis of their relatively

long Bi-O [3.05(2)A] and Bi-Cl p.121(3) A] distances, respectively. These interactions

are responsible for their polymeric lanice arrays, aad the structure of =NO3 only differs

from the hydrated solid _6BN03eH,0Us in that wata adopts one of two anion contacts

- - -- -

Crystal data for =(Me): C,&@N,S,, FW 521 -55, trigonal, space gmup R3 (#146), a = 16.2626(8)& c = 6.579(2)& V = 1506.9(2)A Z = 3.

123 Table 6.1 Selecteâ bond distances (A) for aminoethanethiolates (Bi-CI and Bi-S are

intermolecular contacts).

Figure 6.1 Crystallognphic view of Bi(SCH,CH2NHa, fi.

Figure 6.2 Crystallographic view of Bi(SCH2CH2NH&I =Cl.

Figure 6.3 Cryaallographic view of Bi(SCX,CHJW&Cl m(Me)CI.

Figure 6.4 Crystallographic view of the tetramer of Bi(SCH2CH2NMwl,

K(Me) '/fiCl.

Figure 6.5 Crystallographic view of Bi(SCH2CH2NHMi)Cl, m(Me)CI.

observed in the solvmt fkee structure. In siirprisuig contrast to =Cl, a(Me)Cl has a

substantially shorter (more covalent) Bi-CI interaction [2 -6 1 û(g)A], and is bcst considered

molecular in the solid state aside fiom the intennolecular Bi-S contacts. These

structural differences may be rationalized in ternis of the steric hindrance borne by the

pendant amines in 6&(Me)CI relative to those of the parent ligand. The restricted access

of the amines in m(Me)CI is evident in the Bi-N bond distances m(Me)Cl: 2.84(2)&

2.67(3)A; -NO,: 2.48(2)A; ml: 2.528(9) A, 2.398(8) A], and the comspondingly

weaker auxiliary amine donation in m(Me)Cl enabling a more competitive coordination

of Ci-. The relative withdrawd of the pendant amines in 6B(Me)Cl may be associated

with the distorted cis configuration of the cation moiety, which contrasts the tram

configuration adopted in both -NO, and ml.

The intermolecular interactions (Bi-S) are longest in a enabling an essentially

molecular structure in the solid state, with a distorted pentagonal pyramidal geometry at

bismuth imposed by two cis equatonal sulfbr sites, one apical sulfur site and three

equatorial nitrogen sites, and perhaps irnplicating a stereochernically active lone pair in

the other apical position.

The acyclic structure of rm(Me)Cl contains a six-coordinate, near octahedral

bonding environment for bismuth. A one dimensionai spirocyclic polymeric arrangement

results fiom the association of the bismuth centres by aitemathg chlorine and sui fur

coordinative bridges. The two B i - C i bonds [2.615(4) and 2.636(3)A] are shorter than

the Bi-Clb"@# bonds [2.776(4) and 3.001 (414. Likewise, the Bi-S bond [2.669(3)A]

which is pans to the Bi-Clws is significantly shorter than that which is trons to a Bi-

130 Cl- [2.927(3)A].'" These bond distance cornparisons can be interpreted in terms of

the bismuth center engaging four covalent bonds (tbree chlorine and one sulfùr) (Figure

6.5) and two coordinative bonds (one chlorine and one thioether) h m a neighboring

molecule.

As a demonstration of the potential broad utility of the established synthetic

methods, the antimony analogue (mEC1) of complex -1 has been isolatedb nom an

analogous reaction of aminoethanethiolate with antimony chloride in ethanol and

stnicturally characterized (Figure 6.6). A similar bicyclic arrangement is observed as for

the bismuth complex, but with the complete removal of the chlorine atom fiom the

antimony coordination sphere, giving a rare example of a stibenium cation.

6.3 Conclusions and Future Directions

The homologous series of mono-, bis- and tris- thiolated bismuth complexes

presented above establish the coordinative fiexibility of b i s m u t h o with

aminoethanethiolates and illustrates the ease of stoichiometrically controlling thiolate

coordination chemistry. The pendant amine moieties mediate the high thiophilicity of

bismuth even in the presence of thiolate moieties (raths than thiols) by coordinatively

engaging the bismuth center, so that the stoichiometry of the reaction mixture govems the

degree of thiolation in the isolateci product, thereby overcoming the astoichiornehic

multithiolation, typically encountmd in reactions of bismuth salts with thiols. The

degree of thiolation by the aminoethanethiolate ligand cm be M e r tuned by

manipulating the coordination of the auxiliary amine in two ways: the steric imposition of

Prepared in the Chemîstry 3 101 undergraduate laboratory, Daîhousie University.

Figure 6.6 Crystallographic view of Sb(SCH,CH,NHJCl mC1. Selected bond lmgths

[A]: Bi(1)-S(1) 2.47q6); Bi(1)-S(2) 2.440(6); Bi(1)-N(1) 2.37(2); Bi(1)-N(2)

2.35(2); Bi(1)-Cl(1) 3.577(6).

132 methyl substituents on niîmgen allows for a slightly higher degree of thiolation than the

parent ligand, and the amine can be mtirely uncoupled h m bismuth by protonation, with

retenti on of a mono thiolatobismuth cornplex. These results provide a systematic and

comprehensive series of structuraUy simple thiolatobismuth complexes and the synthetic

approach is Uely applicable to heavy wtals in gend . The potential widespread utility

of the established synthetic methods has been demonstrated in the preparation of an

anthony analogue and the novel bismuth (me&yl~cr)methanethioIates discussed in

Chapter 7.

To date, studies into mixed-thiolate bismuth complexes have not been reported.

Compounds of mixed dithiocarôoxylate ligands have been prepared (Chapter 5.4),

including mixed dithiocarbamate, dithioxanthate, as well a s dithiocarbamate-

dithioxanthate complexes. The controlled thiolation dernonstrateci by the synthesis of the

fmt homologous aminothiolate series suggests a potential for sequential thiolation using

various substituted amine functionaiities:

Ln addition, the aminothiolate ligands could be substitutal for other bihctional thiolate

ligands (e.g. ester-, hydroxy-) to producc mixai functionality compounds:

B is(bihctiona1 thiolate) bismuth sources have been isolated h m aqueous media

[e.g . bismydroxy-/aminothiolato)bismuth nitrates 550/-,] and are potential

intermediates to water stable bismuth carboxylate complexes. One possible reaction

pathway involves Ligand exchange reactioris, such as those employed to prepare

[Bi(SCH,CH20H)S(J (X = CI, Br) 551-52 h m the nitrate salt 550:

OOCR

Also, as bisfiydroxyethanethiolato) bismuth acetate 555 is prepared by recrystallization

of the hydroxythiolate-alkoxythiolate complex 554 h m acetic acid, similar methods may

be emplo yed to prepare other carboxy late analogues:

The high pK,'s and weak chelate abilities of a-amino acids, hydroxycarboxylates

and other simple bifiuictional carboxyIata promote hydrolysis reactions of bismuth in

aqueous media. The above outlined mactions may be expanded and employed to

investigate the structural, spectroscopie and tcaction chemistry of mixed water stable

134 bifunctional carboxylatdthiolate comptexes, incorporating biologically and medicinally

interesting ligands such as glycinate and salicylate:

135 Chapter 7. (Methylester)methinethiolates: The First Ester Complexa of

B i s m u t h o as a Step Toward Modeling ToUoidaI Bismuth Subeltrite'

7.1 Introduction

This chapter descnbes the preparation of the k t ester complexes of bismuthm),

which adopt interrnolecular arrangements maiogous to the ubiquitous dimer structure

observed for citrate complexes of bismuth in CBS 2 û 9 - 1 5 . ~ ' In the absence of

bismuth-ester complexes in the litenhue, section 7.2 introduces the established chemistry

of bismuthtarbonyl compounds. As a backdrop for srnichual discussions, a molecular

orbital mode1 for bismuth complexes is presented in section 7.3.

7.2 Synthesis and Structure of Bismuth-Organocarbonyl Complexes

There are few examples of bismuth compounâs containuig O-carbonyl bound

ligands in the Iiterature, the majonty of which are bihctional and involve ketone and

alkoxide donors. The dipivaloylmethanate compound [Bi(&m),(HdbN] 705 is an

analogue of the ketothiolate [Bi(PhCH {S} CH2C (0)Ph)3 JZICHICIJ 558, which was

discussed in Chapter 5.3. Other sûucturally characterucd compounds include mono- and

polydentate Lewis base adducts. Characterization data is presented in Table 7.1.

Lewis base adducts of bismuth trihalidts are prcpared by direct addition of the

ligand, while bi func tional alkoxides are isolated h m metathesis reactions between bismuth

alkoxides and titanium aikoxides, as well as other cornmon bismuth reactants.

Organobimuth halide adducts (PhBiBr2(dmDia)] and [WBiBr2(dmbir)J have alpo been

prepared and struchrrally charactteruedm

136 Table 7.1 Analytical data for organocarbonyI compounds.

Cornpouad yield X m E s c I R U N M (rxn R p A o o R a V M S

*Svntheses:

7.1) Bi& + n L + Bi&&),

7.2) Bi& + 3 HL + 3 MOH + BiL, + 3 MX + 3 H,O

7.6) BiOJO,), + HL + [Bi(Q(NO,)] + 2 HNO,

7.3) Bi(OR), + HL + Ti(0iQ + Bi(L)(OR'), + Ti(OR)*(OR?, + HOR

7.4) Bi(OR), + HL + Bi(LJ(0Rh + HOR

7.5) BiPh, + 3 HL + BiL, + 3 PhH

The smcture of the cation of the cornplex p i w 6 ] [ B i , I , J 701'~ shows

bismuth in a six coordinate near ocbhedral environment, with al1 six coordination sites

occupied by OBmm ligands p i -O 2.3 lz(8)A; Bi-O-C 1 55.7(8)O]. A bismuth thiolate

&DU adduct [Bi(SC,&),- 5180' has aiso ~CCII structuraîly characterized, and was

discussed in Chapter 5.

701

The monomeric structure of bismuth ethylmaltolate [Bi(emal)J 70P9'

shows a six-coordinate distorted pentagonal bipyrarnidal enWonment for bismuth, with al1

three 0,O '-bidentate Ligands forming five-membered -BiOCCO- rings mi-0- 2.124(7)-

2.250(7)A; Bi-O, 2.420(8)-2.5 1 8(7)A 1. The faciai akoxide oxygen mangement

incorporates the apical site.

702

The aromatic chamcter of the condensed benzene ring of the 4,S-t>enzotropolonato

anion prevents delocalùation of the double bonds in the tropolonate ring (structure

M), allowing the iigand to chelate bismuth in a ketone-alkoxide manner. The bis@#)

complex [Bi@&2(N03)(H20)] 703- shows a six coordinate distortad environment for

bismuth incorporating two 0,O'-tropolonatc ligands [Bi-O, 2.323 and 2.3 1 1 ; Bi-

0- 2.263 and 2.130A~. an O-water molecule [Bi-O 2.621A] and a weakiy coordinated

monodentate nitrate group [Bi-O 2.795Al.

~i,(p-OP~')~(OPf)&f-acac~t]~ 704,'97 a a example of a mixed anionic ligand

cornplex, shows a dimer based onedimcnsionai polyma in the solid state. The six

coordinate bonding environmmt for bismuth is occupied by two pairs of asyrnrnetrically

bridging alkoxide oxygen atoms pi-O 2.19(2) and 2.12(3 ); Bi-O 2.50(2) and 2.69(3)A],

and an ligand [Bi-0- 2.27(3); Bi-& 2.43(4)A 1, forming a six-membered

-BiOCCCO- ring. The i n c d coordination results in very low volatiiity and themal

insbbility of the compound compared to other bismuth dkoxides. Bismuth

tBu acaç

tris(dipivaloyhethanate) (g~ni) pi(dDm)3(HmJ 7 p shows two unique bismuth atoms

each chelated by thm 0.0'- ligands [Bi-O 2.133(7)-2.455(8)A]. A long contact h m a

139 neighbouring molecule pi-O' 3.070(8)A] creates a dimeric structure and gives a seven

coordinate pentagonal bipyramidpl geometry for bismuth. In this case, however, Bi-O and

C-O bond distances do not render an obvious distiaction betwecn the alkoxide and ketone

functionalities in al1 cases.

The trifiinctional OJ,O"-furaldehydohydrazone Lewis base adduct complex

[ s i a 3 C l , ] 706'= [Bi-O- 2.424(8) ; Bi-N 2.654(10); Bi-O* 2.986(9) A] is based on a

faciaily arranged BiCI, unit [Bi- 2.7710); B i C i 2.562(5) and 2.~1q4)Al. A

long chlorine contact pi-CI' 2.909(5)A ] to the w p t y axial site creates a one-dimensionai

polymeric arrangement.

7.3 Secondary Bonding and the tram Effect: the Role of a* Orbitals

The structural features of many bismuth compounds, including the bismuth ester-

thiolates descnbed below, may be rationalized in terms of secondary bismuth bondindm

which warrants a brief defhition. The Lewis ridity and pronounced expansion of the

coordination sphere of bismuth, as well as that of the other heavier p-block elements, was

believed to occur through Iow eacrgy empty dorbitals. Howevcr, calculations suggest

they are too high in mergy to enable significant involvernent in bonding,"' while an

alternative mode1 d s t s the participation of Bi-X a* orbitals. When X is more

140 electronegative than Bi, the antibonding o* orôital will be polarized toward the bismuth

atom:

I

Energy

If this orbital is sufficicntly low in energy it may act as an accepter. The low

electronegativity of bismuth means a higher atomic orbital energy and poorer orbital

overlap with X, resulting in a low energy a* orbital. This model requires a nearly linear

L-Bi-X geometry, and a lengthening of the Bi-X bond as the LBi interaction increases,

due to increased occupation of the a* orbital. This model has been at least qualitatively

usehl in rationalizing the structures of a number of Lewis base adducts of bismuth

phenylbismuth d i h a l i d e ~ , ' ~ ~ ~ as well as the octahedral-bas& structures of Pi(SC,F,),l2-

51 34'6 and the [Bi(SC$,)3(L) J adducts 514-21"' (Chapter 5.2).

7.4 Results and Discussion

Reactions of potassium (methy1ester)methanethiolate with b i s m u t h o chlonde in

95% ethanol at the appropriate stoichiometry give bis[(methylester)methanethiolato]-

bismutho chloride (2: 1) and tris[(me~yle~tcr)rnethanethiolato]bismuth(III)

(3 : 1 ), respectively. Reactions of (methy1ester)methanetbiol with b i s m u t h 0 chloride

also give a which was identified by its distinctive Raman spectnim as the dominant

product, independent of reaction stoichiometry (4: 1,3: 1,2: 1).

14 1 Compowid a adopts a one-dimensional polymeric array in the solid state (Figure

7. l), with hepta-coordination for bismuth imposed by four equatorially disposed sulfur

centers, two oxygen centers (carbonyl) and one chlorine center. The long and essentially

equivalent Bi-S distances mult fiom the strong Pans in.flumcem induced by

intennolecular Bi-S contacts [S(I)-BLS(2a) 154.5(2)' and S(2)-Bi-S(l a) 170.3(1)'].

Although a molecular unit represented by drawing a is indistinguishable in the

polymeric solid state structure, the analogy with the more molecular hydroxy/thio 551'

and amino/thio -)Cl 3*U5us-'89 derivatives is important. The more polymenc structure

of a may be attributed to the restrictions imposed by the backbone sp2 hybridized

carbonyl carbon center and the consequential chelate ring strain.

The structure of the tris(esterthio1ato)biomuth complex a (Figure 7.2) may, at

first glance, be viewed as two trischelated bismuth centers, as observed for the

keto/thio late 5 ~ 8 " ~ and amino thiolate complexes U(R)T9 However, closer inspection

of the Bi-S bond distances [Le. Bi-S(2a). 3.331(2) is substantially longer than Bi-S(2),

2.608(2), Table 7.21 reveals that one of the Ligands clearly functions as an intemuclear

Figure 7.1 Crystallographic view of polym&c ~ r u i g a n m t of [Bi(SCH,COOCH,),C1]

24.

Figure 7.2 Crystallographic view of the dimcric m g c m e n t of [Bi(SCH,COOCH,),)

m.

144

Table 7.2 Cornparison of selected bond lcagths (A) in bismuth-esterthiolate and related

complexes.

CBS

Bi-Cl 3.488(4)

* Average bond distances for two unique molecules.

(&-Bi) bridge, rather than a chelating ligand, imposing a distinct dimer structure m,.

145 In cornparison with the polymeric structure of Z& substitution of the chloride for a third

thiolate is manifested in the dislocation of the . . .S2BiS,Bi.. . chah with consequential

enhancement (shortening) of the three facial thiolate interactions (Table 7.2). The

resulting centrosymmetric dimer mimics the dimenc arrangement evident in citrate

complexes (CBS) 209-15, which is made possible by pendant carboxylate moieties.

0 2 209-15

However, the multiple intemolecular interactions obsenied among dimer units in the

carboxylate complexes are precluded by fornial introduction of the methyl goup to the

carboxylate functionality (to give the ester). The resulting molecular simplicity

highlights the ester fbnctionality as an important stepping Stone to understanding and

controlling the carboxylate chernistry of bismuth.

Preliminary studies have afforded the isolation and structural characterization of a

thiolactate (thiolate-carboxylate) complex of bismuth through similar procedures. The

stoichiometric reaction of BiCI, with thiolactic acid and two equivalents of KOH in

ethanol gave a small crop of crystals of K B i {SCH(CH,)COO}ClJ ZS; (see Figure 7.3).

As with the ester-thiolate complexes, the ligand chelates the bismuth center in an $0-

bidentate manner, however, the carboxylate group also bridges a second bismuth atom in

an 0,O' fashion, giving three coordination contacts for the funetionality. As with

Figure 7.3 Cxystailographic vicw of the polymcric anangcmc1it of

K p i { S C H ( C H ) C Cl] E. Selected bond lmgths [A]: Bi(I )-S(1)

2.5 14(8); Bi(1)-Cl(1) 2.647(8); Bi(l>Cl(2) 2.643(7); Bi(1)-ql) 2.41(2);

Bi(l)-O(1 a) 2.5 l(2); Bi(1)-û(2a) 2.74(2); IC(1)-û(2a) 2.70(2).

147 the thiosalicylate complex 548, intermolecular bonding occun solely through the

carboxylate group, with no long sulfur or chlorine contact.

7.5 Conclusions and Future Direction

Despite the relatively low basicity of the ester (carbonyl) (pK, 21.5; cf. OH p&

16.5, NR, pi&, 9.2. CO; pK, 9.2), the pendant donor intemolecular arrangement

observed for 'colloïdal bismuth subcitrate' has been modeled by anchorhg the Ligand on

bismuth via a thiolate tether. In this way, bifùnctional ligands offer synthetic venatility

to study the interaction of bio-relevant fhctional groups with bismuth, and the hydrolytic

stability of the thiobismuth unit allows for manipulations and observations in aqueous

media.

Additionally, the ester functionality provides a simpler bonding mode1 for the

carboxylate group, which typically chelates bismuth in an 0,O'-manner. In monodenate

carboxylate bonding situations, exocyclic carbonyl oxygen atoms are typically involved

in intermolecular bndging, as observed for lç. bismuth arninocarboxylates (Chapter 4)

and CBS. The introduction of an organic group in the neutral ester huictionality deters

the second (ether) oxygen atom h m possible intra- and intermolecular bonding, and

allows for limited intennolecular coordination.

The amide [C(O)NR,] functionality has the potentiai to accommodate an

intermediate number of intermolecular interactions between those of the carboxy late and

ester complexes. Replacement of a carboxylate oxygen atom with an amine group allows

for both monodentate and N,O-chelating bonding situations, with limited (one)

coordination to the amine hgment. As with ester-thiolate complexes, bifûnctional

148 amide-thiolate ligandsw2 are a rational route to the preparation of bismuth-amide

complexes. Establishing bonding relationships between carboxylate, ester and amide

fiinctionalities is crucial when derivatization of more complex carboxylates are

considered.

The solubilization of bismuth citrate under basic conditions is likely due to

deprotonation of the hydroxy- p u p of the (Hm3- ligand (to fonn the alkoxide) and the

subsequent tridentate chelation of the ligand to thc bismuth center (Chapter 2). Further,

the solubility of the resulting stxucture may be mhanced by the negatively charged

pendant carboxylate group. A comprehensive assessrnent of the role of individual

fùnctional groups of citrïc acid on detmniaing the physical properties of CBS may be

possible through sequential derivatization (structure X: RI, R2, R~ = OMe, NH3,

replacement (structure X: R4 = NHa or removal (cg. malic acid, tricarballylic acid).

Further, and as described in Chaptcr 4, m a s spectrornetry may be employed to study

soluble species.

citric acid X

maiic acid tricarballylic acid

149 The focus of this thesis lies in the interaction of bismuth with organic fiinctional

groups outhed in Chapter 1, howcver, there are several "inorganic" hctionalities which

are comrnonly mcountered in biologicai systenis. The established bihctional ligand

approach may be extended to incorporate highly oxidized main p u p atoms such as

nitrogen (nitrate), phosphorus (phosphate, phosphohate) and sullur (sulfate, Wonate).

nitrate phosphate sulfate

phosphonate sulfonate

The highly acidic nature of these bctionalites pcmiits sufficiently low pH conditions to

deter bismuth hydrolysis reactions and suitable media for simple metathesis teactions in

aqueous media. nie utility of these ligands has been demanstrated by the reaction of

bismuth nitrate and the bihctionai phosphonat~-~arboxylate in water to give

[si(0,PC,H,CO&H20)] 707 or acetone to give the pmtonated

~iH(03PC2H,CO&(H20)] 7 0 8 . ~ Structurai studies of 707 reveals the phosponate

150 functionality bndging three bismuth centers and weakly chelating a fourth. Similar

stnicniral studies may unveil novel bonding situations and intriguing srnichiral

arrangements.

Chapter 8. Experimental

8.1 General Procedures

Melting points wem recordeci on a Fisher-Johns melting point apparatus and are

uncorrected. IR spectta were recorded as Nujol mulls on Cs1 plates using a Nicolet 5 10P

spectrometer. Raman spectra were obtained for powdered and crystalline samples on a

Bniker RFS 100 spcctrometer. Chemicd analyses were perfomed by Canadian

Microanalytical Service Ltd., Delta, British Columbia Solution 'H and "C NMR data

were recorded on a Bruker AC-250 spectrometer. Chernical shifts are reporteci in ppm

relative to and are calibrateci to the intaal solvent signal. Mass spectra were

obtained using a VG Quattro triple quadrupole m a s spectrometer (VG Organic).

Atmosphenc pressure chemical ionkation (APCI) samples were saturated

solutions in 95% ethanol[69. aN0,], acetonitrile [S50-52,555, fi(Me), m(Me)Cl],

dimethyl formamide mC1, =(Me). YiHCl, W e ) ] or dimethylsulfoxide [7A. 7B 1.

Solvent flow [ 1 00% acetonitrile (95% ethanol for 6& 48NOJ at 300pUmin] used a

Shirnadni LC-I OAT liquid chromatograph pump with a Rheodyne syringe loading

sample injector.

8.2 Synthetic Procedures

Bismuth chlonde, bismuth oxychloride, bismuth nitrate pentahydrate, antimony

chloride, 2-aminoethanethi01 hydrochloride, Nfldimethylaminoethanethiol

hydrochloride, methylthioglycolate, glyoxylic acid and thiolactic acid were used as

received fiom Aicirich. Aminoethanethiol (cysteamine) ws used as received h m Fluka.

152 Oxalic acid was used as received h m Fisher. N&,N 'a '-&y lenediwllnetetraaci tic acid

and potassium hydroxide were used as rcceived b m BDH. AU reactions involving

thiols were performed under an atmosphere of N, (to prevent the oxidation of thiols to

disulfides) using standard Schlenk techniques, with the exception of the preparation of

compound m(Me)Cl and Q(Me)Br. Ail compounds are air stable, although 6&Me)CI

changes colour over a perïod of weeks and =Cl is light sensitive. For compound

oD(Me)Br, the dimethylaminoethanethioi hydrobromide sdt is prepand in situ by -

reaction the chloride sait with AgNO, in the appropnate reaction solvent, filtration to

remove AgC1, addition of NaBr and filtration (in the case of the ethanol reaction) to

remove undissolved materials.

The syntheses of [Bi,(~0,)Jm8H20 3& which has been prepared by various

methods, Sb(SCH2CH2NHJC1 mC1 and K p i {SCH(CH,)COO} Cl,] 7C are preiiminary

results and have been attempted only once. Characterization of each is limited to single

crystal X-ray difhction data, which is of poor quality for =Cl. Samples of a contained crystals of varying habit (needles, blocks), not al1 of which were identified.

Thiolate Complexes

The thiolate compounds described below w m prepared by a general procedure,

with the specific conditions for isolation presented in Table 8.1. Between 3 and 10 mm01

of solid bismuth reagent PiCl,, BiBr,, Bi(NO,),.SH,O or SbCl,] was added to a solution

of an aminoethanethiol (parent or dimethyl derivative), an aminoethanethiol

hydrochloride, an aminoethanethiol hydrobromide (generated in situ) or a mixture of an

aminoethanethiol, methylthioglycolate or thiolactic acid with KOH, in 95% ethanol,

153 acetone or wata (150 mL), or glacial acetic acidhvater (6mV14mL). Most reactions are

instantaneous giving yellow solutions (colorless for =Cl), which were stirred ovemight,

filtered and reduced in volume on a rotary evoporator (95% ethanol or acetone) or a hot

water bath (water), until precipitation began. The solution was then re-filtered and cwled

on ice, in the refiigerator (4'C) or h z e r (cO'C), or lefi to evaporate slowly to give

crystalline materials (Table 8.1). Isolateci samples were washed with ethanol, acetone and

ether (25mL each) and dned under vacuum for one hour. Characterization and

spectroscopie data are presented in Tables 8.2-8.4.

Equirnolar reaction mixtures of BiC1, with KSCH,CH,NMe, (7mmo1, prepared in

situ) in 95% ethanol (lSOmL) gave a low solubility powder, which was extracted fkom

the reaction precipitate with dmfand rccrystallizcd by removal of sotvent in vacuo.

Crystals of 6C(Me)* '/JICI were reproducibly Pasteur separated nom a crystalline

mixture and were characterizcd by X-ray crystallography, but data for the bulk sample

were not reproducible. Although the rolubility of compound mr(Me)Cl is very low,

smail samples were crystallized h m aqueous solution and shown to have the same

identity as the bulk reaction mixture prccipitate by a variety of techniques. The bromide

analogue oe(Me)Br was isolated as a powder oniy. Compound a was isolated as a

powder fiom the reaction mixture and rccrystailùed fhm Pmf under vacuum (yellow

needles).

Table 8.1 Reaction and isolation conditions for thiolate complexes.

C o m p o d Reagents, solvents and Crystal Comments amounts (g, mmol) isolation and

pend 6A - BiCl, (1.04,3.35) 4OC, 4 &YS

KOH (1 .88,33.5)

95% ethanol(150 mL)

Ume) BiCI, (2.10,6.64) 4OC, 3 days

KOH (2.24,39.9) 9

95% ethanol(150 mL)

6BNO, Bi(NO,)pSH,O (2.44,s .O3) - ice, 2 hours

HSCH,CH2NH2 (0.78, 1 0)

KOH (0.56, 10)

water (150 mL)

6BNO, Bi(NO,),.SH,O (2.52,5.20 ) - evaporation, light excluded

mH,O HSCH2CH2NH, (1.20, 15.6) 4 days no preconcen tration

KOH (0.875, 15.6) of reaction filtrate

water (1 50 mL)

6BC1 - BiCI, (3.02,9.57) evaporation, light excluded

HSCH2CH2NHpHC1 (326.28.7) 4 days

KOH (3.22,57.4)

95% ethanol(150 mL)

6B(Me)C1 BiCl, (2.09,6.64) - 4OC, 1 day

HSCH2CH2NMe,*HCl (1.88.13.3)

KOH (1 -49.26.6)

acetone (1 50 mL)

155 Table 8.1 Reaction and isolation conditions for thiolate complexes (continued).

Compound Reagents, solvents and Crys ta1 Comments amounts (g, rnmol) isolation and

p e n d

6D(Me)CI BiCl, (2.10,6.64) - precipitation BiCl, dissolved in

1) HSCH,CH,NMepHCI (1.88, 13.3) THF and added

95% ethanol(150 mL), üif(5ûm.L) dropwise to ligand

solution

2) Bi(NO,),.SH,U (2.43, 5.01) precipitation ligand added to

HSCH,CH2NMepHCI(2. 13,lS.O) solution of

water (14 mL)/ acetic acid (6mL) Bi(NO,),eSH,O

bulk sample

isolated as powder

3) crystals h m water wash of evaporation,

reaction mixture precipitate of (2) 12 days

6D(Me)Br BiBr, (2.98,6.64) - d a HSCH,CH,NMep

1) HSCH,CH2NMepHCl (1.89, 13.3) HBr generated in

AgNO, (2.50, 14.7) situ

NaBr (1 .S 1, 14.7)

95% ethanol(l50 mL), thf(5ûmL)

2) Bi(NO,)pSH,O (2.43.5.01) d a HSCH,CH,NMep

HSCH,CH,NMepHCl (2.1 3, 15.0) HBr generated in

AgNO, (3.00,17.7) situ

NaBr (1.82, 17.7)

water (14 mL)/ acetic acid (6mL)

6EC1 - SbC1, (0.91,4.0) <O0C

HSCH,CH,NH,~HC1(1.36,12.0)

KOH (1.36,24.2)

156 Table 8.1 Reaction and isolation conditions for thiolate complexes (continued).

Compound Reagents, solvents and C V ~ Comments amounts (g, mmo1) isolation and

pcriod

7A - BiCI, (1.67,5.28) fiom DMF light excluded

HSCH,COOMe (1.12, 1 0.6) under vacuum

7B - BiC1, (1.65,5.23) 4"C, 1 day

HSCH,COOMe (1.67, 15.7)

KOH (0.88, 16)

95% ethanol(150 mL)

7C - BiCl, (1 .00,3.16) 4OC, 1 day

HSCH(CHJCO0H (0.3Q2.8)

KOH (0.33,S.g)

95% ethanol(1SO mL)

Bismuth Oxulate Octuhydrate ~i&O,) , ].8H20

BiCl, (0.53g, 1.7mmol) and oxalic acid (4.5 1 g, 50.1 mmol) in water (40mL) were

refluxed for 1 1 hours then hot filtered to remove unreacted materiai. Colorless needles of

3A appeared on cooling in air and w m collected &a 2 days. Also prepared by a similar - reaction, replacing BiOCl for BiC1,(1 .mg, 3.84mmol); oxalic acid (3.ûûg, 33.31~101);

water (100mL); reflux period 7 hours; crystallization period 4 &y; crystals remained

under reaction solution until X-ray data collection. Also prepared by a similar reaction,

replacing glyoxylic acid for oxalic acid(Sg, Sx 10-hol); BiCl, (0.5 1 g, 1.6mmol); water

(1 OmL); reflux period 12 hours; crystallization period 6 days; crystals remained under

reaction solution until X-ray data colfection.

Hydrogen Bis(Bismuth Hydrogen A(N.N. N: N'-ethylenediaminetetraacetate) Chlonde

Dihydrate (pi(HEDTA)],H) Cl@2H,O a

BiCl, (1.08g, 3.42mmol) added to ethylenediarninetetraacetic acid (1.00g, 3.42mmol) and

KOH (0.57g, l0mmol) in water ( l50ml) was allowed to stir overnight. The solution was

filtered and concentrated to 40mL over a hot water bath. Colorless needles of a appeared on cooling, collected fier one &y evaporation in air.

Table 8.2 Yields and elemental analyses for dl compounds.

Compound Yield [g, m o l , %] Elernental analysis 1% calc (found)]

6Aow 0.75, 1.4,22 C: 27.63 (27.74) H: 5.80 (5.63)

N: 8.06 (7.99)

6BN03 - 0.48, 1.5,23 C: 1 1.35 (1 1 .40)

H: 2.86 (2.84)

N: 9.93 (9.96)

6BN03*H20 - 0.79,2.4, 35 not determineci

6BC1 - 0.64, 1.6, 17 C: 12.1 1 (12.28)

H: 3.05 (3.00)

N: 7.06 (6.86)

6B(Me)C1 - 0.94,2.1, 3 1 C: 21.22 (21.16) H: 4.45 (4.36)

N: 6.19 (6.04)

159 Table 8.2 Yields and elemental analyses for al1 compounds (continued).

Compound Yield [g, mmol, %] Elmental analysis [% calc (found) J

6D(Me)Cl - 1) 2.72,6.47,97 C: 1 1.42 (1 1.98)

H: 2.62 (2.77)

N: 3.33 (3.42)

2) 1.41,3.35,67 C: 1 1.42(11 .52) FI: 2.62 (2.64)

N: 3.33 (3.32)

3) 0.05, O. 1,2 C: 1 1.42 (1 1.57) H: 2.62 (2.79)

N: 3.33 (3.32)

6D(Me)Br 1) - >95% C: 8.67 (9.19)

H: 2.00 (2.07)

N: 2.53 (2.57)

8.3 Physical and Spectroscopie Data

Table 8.3 Complete vibrational data for al1 compounds.

Compound IR data (cm") Raman data (cm")

4A - 444m, 472w, 496w, 5 MW, 8 ls, 95vs, 136s, 152s, 172s, 204s,

542w, 562w, 592w, 608w, 2281x1, 275w, 293w, 361m, 380x11,

660w, 696w, 770w, 856m, 922s, 407m, 448m, 485m, 581w, 63%,

958m, 9 8 b , 1002w, 1040w, 667w, 71 Sw, 734w, 830w, 920w,

1054w, 1094m, I l lûw, 1170w, 973w, 998w, 1037w, 1 0 5 4 ~ ~ 1098w,

1224w, 1 2 5 4 ~ ~ 1302w, 1318w, 1167w, 1 2 2 5 ~ ~ 125ûm, I302w,

1598s, 1 6 3 4 ~ ~ 1726rn 1324m, 1340w, 1383m, 1437m,

1472m, 1593w, 1629m, 2852w, 291 Os,

2937s, 2958s, 2984m

6A - 290vs, 3 15vs, 4 1 1 s, 487s, 505m, 1 OOvs, 123vs, 177vs, 2 1 1 s, 256m, 286s,

658m, 722w, 82 1 w, 832111, 321s, 663m, 832w, 902w, 944w, 976w,

904w, 940w, 1020w, 1065w, 1021w, 1 0 6 5 ~ ~ 1108w, 1 2 1 0 ~ ~ 1 2 6 7 ~ ~

1 106m, 1208m, 1264w, 1289w, 1298w, 1378w, 1 4 1 9 ~ ~ 1449m,28 18w,

1301w, 1579m,1609w 2849m, 2900s, 29 13s, 2924s, 3 1 53w,

3244m, 3294w

6A(Me) 232w, 266vs, 346m, 415s, 437w, 7ûw, 112s, 162s, 233w, 270vs, 352m, - 522w, 662m, 723w, 762vs, 417w, 437w, 523w, 663m, 764w,

893vs, 95 1 m, 1002s, 1038m, 894w, 953w, 1003w, 1û40w, 1062w,

1060m, 1 0 9 8 ~ . 1 125w, 1 154s, 1 1 2 6 ~ ~ 1 156m, 1218w, 1 2 4 8 ~ ~ 1292m,

121Sm, 1245w, 126Sw, 1291s, 1367w, 1402w, 1432m, 1448m, 1467w,

1 4 0 1 ~ 2 5 7 5 ~ , 2 6 4 8 ~ ~ 27-, 2785~, 2800m7

28 16m, 2850m,29 19s, 2943m, 2980m

16 1 Table 8.3 Complete vibrational data for al1 compounds (continued).

Compound ïR data (cm-') Raman data (cm-')

6BN0, 264vs, 300w, 329m, 469s, 61 8s, 1 14vs, l92m, 216s, 268vs, 282s, 350vs, - 666m, 703w, 723w, 822% 475w, 667w, 712w, 841 w, 92 1 w,

839m, 919m, 968s, 1035s, 1037s, 1066w, 1223w, 1273w, 1381w,

1074m,1221w, 1268w, 13 lgm, 1424w, 1454w, 1572w, 164Sw, 2661w,

1426w, 1573s 2737w, 2828w, 2874m, 291 lm, 2932s,

2948m, 3233w, 3308w

6BCl - 244s, 28 lm, 3 l7s, 330m, 370w, 66vs, 90vs, 106vs, 124vs, 172s, 212vs,

461s, 477m, 589w, 657m,664w, 246vs, 279vs, 322vs, 371vs, 462w,

675w, 722vs, 83 lw, 840w, 591w, 664rn, 83 lw, 845w, 921w,

9 18m, 964s, 101 lm, 1050rn, 963w, 1008w, 1054w, 1081w, 1 103w,

1082m, 1109w, 1155w, 1170w, 1118w, 1214w, 1232w, 1273w, 1289w,

1215w, 1226w, 1275w, 128%. 1372w, 1388w, 1412w, 1426w, 1450w,

1307w, 1412w, 1585w 1587w, 2728w, 2755w, 2830w, 2850m,

2909s, 2919s, 2935m, 2947m, 29561x1,

3098w, 3229w, 3314w

6B(Me)C1 22lvs, 2 9 1 ~ s ~ 358s, 41 ls, 426s, 88m, 103s, 125s, 171m, 21 Ss, 299vs, - 435s, 520s, 661s, 723s, 753vs, 360s, 412w, 438w, 457w, 521w, 664m,

761vs, 894vs, 940s, 951w, 992s, 762w, 895w, 942w, 995w, 1 122w,

1026m, 1039rn, 105ûw, 1097w, 1 160m, 1213w, 1245w, 1297111, 1370w,

1 1 19rn,11 S2m, 1 15%, 1210m, 1403w, 1428m, 1448m, 2723w,

124Srn,l263w, 1291rn,1400w 2787m. 2805m, 2833s, 2869s, 29 1 Os,

2923s, 2953s, 2987m

1 62 Table 8.3 Complete vibrational data for al1 compounds (continued).

Compound IR data (cm-') Raman data (cm-')

6D(Me)Cl 303w, 335m, 41 lw, 5 13w, - 107vs, 127vs, 172s, 220s, 247vs, 334s,

662w, 722m, 756w, 83Sw, 4 12w, 446w, 5 14w, 663m, 757m,

88Sw, 926s, 967w, 101 lm, 885w, 927w, 967w, 101 lw, 1037w,

1035~,1048~,1117w,1149w, 105Ow,12~3w,1229w,1258w,1305w,

1211~,1226~,1256~,1305w, 1365w,1385m,1431m,1451m,

14û4w, 142% 2896w, 2939s, 2955s. 2 9 9 1 ~ 3020m,

3032m

6D(Me)Br S13s, 588m, 658w, 721w, 752w, 75vs, 101m, 1 19vs, 144m, 162vs, - sh, 774s, 834m, 866m,893w, 210vs, 300w, 328s, 408w, 444w, 513m,

922m, 965w, 1 007m, 1 03 1 w, 660m,753m, 878m, 924w, 967w,

1045w, 11 17w, 1 145w, 1 l%Om, 1008w, 1033m, 1045w, 1 117w, 1 147w,

1226w, 1256w, 1321s, 1340~11, 1212w, 1227w, 1257w, 1302w, 1359m,

1425w, 1513vs, 1570vs, 1623vs, 1377rn, 1394w, 1427m, 1451m,

1639w, 3402vs 1464w, 147Sw, 284 1 w, 2893w, 2932w,

2947s, 2960s, 2983w, 302ûm, 3074w

6BNO, 258vs, 285vs, 347m, 481s, - 86vs, 1 17s,153w, 187m, 2 1 Os, 268vs,

eH,O 662m, 688w, 722w, 823s, 839111, 287vs, 359vs, 478w, 665w, 713w,

921 m, 966m, 1045s, 1 082m, 8 4 h , 922w, 96 1 w, 1 û45s, 1 076w,

1 1 12w, 1223s, 1 4 2 5 ~ s ~ 1602s, 1 1 12w, 1222w, 128ûw, 1294w, l338w,

1636s, 175Sw 1385w, 1423w, 1451 w, 1598w, 2744w,

2860w, 2924m, 2964w, 3 154w, 3237w,

3297w

7A - 555w, 681w, 770w, 874s, 886w, 95vs, 1 17s,sh, 147s, 187s, 227vs,

986m, 994m, 1 ldlm, 1206m, 260vs, 350m, 399w, 561w, 686w,

1296m, 13 18m, 1676s, 1 707s 768w, 888m, 984w, 1 M W , 1204w,

1325w, 1376w, 1392w, 1428w, 1673w,

2903s, 2940m, 2959rn,3044w

163 Table 8.3 Complete vibrational data for dl compounds (continued).

Compound IR data (cm-') Raman data (cm-')

7B - 569m, 583m, 681 w, 71 lm, 95vs, 146m, 195m, 22 lm, 266vs,

772w, 864m, 88Uw, 889m, 292vs, 334m, 402w, 580w, 714w,

899w, 90%, 992s, 1 OZlw, 769w, 885w, 908w, 990w, 1 1 5 l w,

1141m,1204s, 1287~~ 1308s, 11 81w, I296w, 1397w, 1435w, 1696w,

1397m, 1434s, 1558w, 1579w, 2886s, 2956m, 2976m, 2988m, 3034w

1605w, 1623w, 1691m,173Srn

1 64 Table 8.4 Melting points, prominent APCI-MS peaks, and 'H and "C NMR data for al1

cornPound mp NMR ( D ~ s 0 - d ~ " APCI-MS

(Oc) ' H 13C [Cone Voltage: m/z (% rd . intensity) J

4~ [2971 - - - - 6A - 87 2.24,3.00, 31.0, SV: 209(100), 361(48)

3.57 47.6 30V: 209(24), 36 l(100)

6A(Me) 140 2.31,2.80, 25.3, SV: 209(1ûû), 417(7) 3.53 44.9, 30V: 209(23), 41 7(100)

65.8

6BNO, - 11581 3.78,3.96, 30.3, SV: 361(100) 4.13 49.1

6BN0, - - - w 3 1 ref Us

*H,O

6 x 1 - 11911 3.77,3.96 30.3, 10V: 209(89), 320(54), 393(100)

49.0 30V:284(75),320(100),393(7)

6B(Me)C1 [125] 2.76,3.50, 26.1, SV: 209(100), 417(2), 453(2) - 4.32 44.9, 30V: 209(25), 348(100), 41 7(5 l),

66.9 453(2)

6D(Me)Cl [205] 2.77.3.30, 23.2. 10V: 2O9(l OO), 348(79), 384(9), 41 7(4), - 4.98,9.02 42.7, 421(57), 453(4)

60.8 30V: 209(10), 348(100), 384(4),

4 1 7(3)

* Decomposition occurs over a broad range and the temperature given represents the

onset of blackening.

** Signals are generally poody resolved.

165 Table 8.4 Melting points, prominent APCI-MS pcaks, and 'H and "C NMR data for al1

cornpounds (continued).

Compound mp NMR (DMsO-d~" APCI-MS [dpl' (OC) 'H "C [Cone Voltage: m/z (% rel. intensity)]

175.8

* Decomposition occurs over a broad range and the temperature givm repments the

onset of blackening.

** Signals are generaily poorly resolved.

166 Table 8.5 Peak assignments of the APCl mass spectra of bis(hydroxyethanethîo1ato)-

bismuth sale [Bi(SCH,CH,OH)&'J.

X cone voltage 1 OV cone voltage 30V

m/z (%) assignment m/z (%) assignrnent

NO, 285 (9) [-BiSqH40-J+ 241 (3) [Bis]'

Table 8.6 M S M assignments for bis(hydrOxyethanethioIato)bimuth(III) salts

Daughters cone m/z (%) of(dz) vo l tage0

- --

NO, 326 10 209 (18) Bi'

550 241 (78) [BIS]'

285 (100) [-BiSC,H40-1'

326 (32) [-BiSC,H,O-+NCCH,]'

NO3 363 10 209 (22) Bi'

550 241 (43) [Bis]'

CI 321 10 209 (28) Bi'

Cl 362 10 209 (12) Bi' -

241 (45) [BIS]'

285 (100) [-BiSC,H,O-]'

321 (48) FI-SC2H40H]+

361 (26) mOC2H4SBiCl + NCCH,]'

8.4 X-ray Crystallography Data

Table 8.7 Crystallographic data for dl complexes.

- -

empirical formula C,H,&O, c,0&2iC1,SO&09

Formula Weight 826.14 534.45

crystaI description yellow, needle colorless, needIe -

crystal system triclinic rnonoclinic

space group P-1 (#2) CUc (#Ils)

a CA) 9.370(3) 25.203(6)

b (4 1 1.106(3) 8.979(4)

Z value 2 8

Qak W m 3 ) 3.180 2.453

R; k 0.03 7; 0.040 0.036; 0.040

Goodness of Fit 1.44 1.64 Indicator

Table 8.7 Cxystallographic data for compounds (continued).

a mBNQ 6Bc1 empirical formula C a , ,BiN3S3 C4H&i%0,S2 C,H,,BiCN2S,

Formula Weight 437.39 423.26 396.71

crystal description yellow, needle needles light yellow, needle

crystal system monoc h i c trigona1 triclinic

space group P2,h (M4) P3,21 (#152) P-1 (#2)

a (4 5.69(1) 8.933 1(10) 8.747(2)

b (4 11.614(9) 8.933 l(10) 9.63 6(2)

C (4 19.562(3) 12.156(4) S.98Cyl)

Z value 4 4 2

O& Wcm3) 2.249 2.5 10 2.67 1

R; ka 0.043; 0.050 0.037; 0.045

RI; ~ l 3 . 2 ~ 0.0669; O. 1526 ~I-OJ

RI; wIUb 0.0683; 01527 (ail data)

Goodness of Fit 1.23 5.157 1 .O7 Indicator

170 Table 8.7 Crystallographic data for al1 compoimds (contiaud).

Formula Weight 452.81 393.19 420.54 --

crystal description long yellow, blocks yeiiow, square- plate needle-like

crystal system monoclinic teiragona1 monoclinic

space group pz1 (#4) 1-4 (#82) P2,k (#14)

a (A) 8. 122(3) 1 5.082(5) 6.850(2)

b (4 1 O, 1 07(2) 1 5 .082(5) 1 3.977(2)

Z value 2 8 4

Goodness of Fit 1.14 2.8 1 4.3 1 Indicator

Table 8.7 Crystallographic data for ail compounb (continued).

=ci* 7A empirical formula C,H,,CN2S2Sb C&,BiClO,S,

Formula Weight 309.48 454.70

crystal description colorless, needlc light yellow, needle

crystal system rnonoclinic monoclinic - space group P 2 , h (#14) Pa (#7)

a (A) 5866(2) 8.092(2)

Z value 8 2

Qd. (%cm3) 3.13 1 2.579

R; R, 0.082; 0.080 0.036; 0.027

Goodness of Fit 4.94 1.57 Indicator

172 Table 8.7 Crystallographic data for dl wmplexcs (continued).

28 x empirical formula C&l,,BiO,S, C,H,BiCl,KO,S

Formula Weight 524.36 423.1 1

crystal description yellow, needle colorless, needle

crystal system triclinic monoclinic

space group P-1 (#2) P2,k (# 1 4)

Z value 2 4

Goodness of Fit 1.60 1.18 Indicator

* Prelirninary structure.

a R = ~ll~ol- I F C ~ ~ I CIFOI; = [ Z W ( ~ O ~ - I F C ~ ) ~ 1 ZWFO~I

2 2 K RI = CI(Fo1- (Fc(l/ ZIFo(; wR2 = {C[W(F~-FC~)~] 1 Z[w(Fo ) 1)

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